ClinVar Genomic variation as it relates to human health
NM_182916.3(TRNT1):c.1246A>G (p.Lys416Glu)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_182916.3(TRNT1):c.1246A>G (p.Lys416Glu)
Variation ID: 963695 Accession: VCV000963695.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p26.2 3: 3148095 (GRCh38) [ NCBI UCSC ] 3: 3189779 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jul 16, 2020 Apr 15, 2024 Jan 16, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_182916.3:c.1246A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_886552.3:p.Lys416Glu missense NM_001302946.2:c.1186A>G NP_001289875.2:p.Lys396Glu missense NM_001367321.1:c.1246A>G NP_001354250.1:p.Lys416Glu missense NM_001367322.1:c.1246A>G NP_001354251.1:p.Lys416Glu missense NM_001367323.1:c.1246A>G NP_001354252.1:p.Lys416Glu missense NR_159934.1:n.1324A>G non-coding transcript variant NR_159935.1:n.1324A>G non-coding transcript variant NR_159936.1:n.1130A>G non-coding transcript variant NR_159937.1:n.2366A>G non-coding transcript variant NR_159938.1:n.1130A>G non-coding transcript variant NR_159939.1:n.1185A>G non-coding transcript variant NR_159940.1:n.1199A>G non-coding transcript variant NR_159941.1:n.2366A>G non-coding transcript variant NC_000003.12:g.3148095A>G NC_000003.11:g.3189779A>G NG_016864.2:g.36623T>C NG_041800.2:g.26180A>G LRG_1314:g.26180A>G LRG_1314t1:c.1246A>G LRG_1314p1:p.Lys416Glu - Protein change
- K396E, K416E
- Other names
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- Canonical SPDI
- NC_000003.12:3148094:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00006
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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TRNT1 | - | - |
GRCh38 GRCh37 |
550 | 677 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 16, 2024 | RCV001237758.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV001249658.5 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa and erythrocytic microcytosis
Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome
Affected status: yes
Allele origin:
germline
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Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV001423622.1
First in ClinVar: Jul 25, 2020 Last updated: Jul 25, 2020 |
Comment:
[ACMG/AMP: PM2, PM3, PM_PS3] This alteration is absent from or rarely observed in large-scale population databases [PM2], is detected in trans with a known pathogenic … (more)
[ACMG/AMP: PM2, PM3, PM_PS3] This alteration is absent from or rarely observed in large-scale population databases [PM2], is detected in trans with a known pathogenic variant [PM3]. (less)
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Pathogenic
(Jan 16, 2024)
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criteria provided, single submitter
Method: clinical testing
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Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001410532.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 416 of the TRNT1 protein … (more)
This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 416 of the TRNT1 protein (p.Lys416Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of TRNT1-related conditions (PMID: 25193871, 29358286, 33332575, 33646446; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 963695). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TRNT1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect TRNT1 function (PMID: 25193871). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Apr 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome
Affected status: unknown
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002498623.2
First in ClinVar: Apr 11, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change in TRNT1 is predicted to replace lysine with glutamic acid at codon 416, p.(Lys416Glu). The lysine residue is evolutionarily conserved (100 vertebrates, … (more)
This sequence change in TRNT1 is predicted to replace lysine with glutamic acid at codon 416, p.(Lys416Glu). The lysine residue is evolutionarily conserved (100 vertebrates, UCSC), and is located in a helical region with an annotated function. There is a small physicochemical difference between lysine and glutamic acid. The highest population minor allele frequency in gnomAD v2.1 is 0.01% (2/19,944 alleles) in the East Asian population, which is lower than the credible allele frequency for a recessive condition. This variant has been detected in at least six individuals (from five families) with periodic fevers, developmental delay, and varying degrees of anaemia with B-cell immunodeficiency. Of those individuals, five were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and four of those were confirmed in trans by parental/family testing (PMID: 25193871, 29358286, 32371413, 33332575; Doi: 10.51271/jpea-2021-0110). Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/6 algorithms predict benign). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM3_Strong, PM2_Supporting, PP1. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Etanercept as a successful therapy in autoinflammatory syndrome related to TRNT1 mutations: a case-based review. | Orlando F | Clinical rheumatology | 2021 | PMID: 33646446 |
Neutrophilic dermatosis: a new skin manifestation and novel pathogenic variant in a rare autoinflammatory disease. | Bardou MLD | The Australasian journal of dermatology | 2021 | PMID: 33332575 |
Disease-associated mosaic variation in clinical exome sequencing: a two-year pediatric tertiary care experience. | Miller CR | Cold Spring Harbor molecular case studies | 2020 | PMID: 32371413 |
Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors. | Giannelou A | Annals of the rheumatic diseases | 2018 | PMID: 29358286 |
Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD). | Chakraborty PK | Blood | 2014 | PMID: 25193871 |
Text-mined citations for rs199931785 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.