NM_001065.4(TNFRSF1A):c.334G>A (p.Val112Met) AND TNF receptor-associated periodic fever syndrome (TRAPS)

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 10, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000823924.8

Allele description [Variation Report for NM_001065.4(TNFRSF1A):c.334G>A (p.Val112Met)]

NM_001065.4(TNFRSF1A):c.334G>A (p.Val112Met)

Gene:

TNFRSF1A:TNF receptor superfamily member 1A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12p13.31

Genomic location:

Preferred name:

NM_001065.4(TNFRSF1A):c.334G>A (p.Val112Met)

HGVS:

NC_000012.12:g.6333505C>T
NG_007506.1:g.13591G>A
NM_001065.4:c.334G>AMANE SELECT
NM_001346091.2:c.10G>A
NM_001346092.2:c.-244G>A
NP_001056.1:p.Val112Met
NP_001056.1:p.Val112Met
NP_001333020.1:p.Val4Met
LRG_193t1:c.334G>A
LRG_193:g.13591G>A
LRG_193p1:p.Val112Met
NC_000012.11:g.6442671C>T
NM_001065.3:c.334G>A
NR_144351.2:n.596G>A

Protein change:

V112M

Links:

dbSNP: rs201753543

NCBI 1000 Genomes Browser:

rs201753543

Molecular consequence:

NM_001346092.2:c.-244G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001065.4:c.334G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001346091.2:c.10G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_144351.2:n.596G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: TNF receptor-associated periodic fever syndrome (TRAPS) (FPF)
Synonyms:: Familial Hibernian fever; Tumor necrosis factor receptor-associated periodic syndrome; TNF receptor-associated periodic syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007727; MedGen: C1275126; Orphanet: 32960; OMIM: 142680

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Chain B, Peripheral plasma membrane protein CASK
Chain B, Peripheral plasma membrane protein CASK
gi|66360665|pdb|1Y74|B

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000964798	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 10, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000964798

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 10, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000964798.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TNFRSF1A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 234422). This variant has not been reported in the literature in individuals affected with TNFRSF1A-related conditions. This variant is present in population databases (rs201753543, gnomAD 0.01%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 112 of the TNFRSF1A protein (p.Val112Met).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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