3-14141704-A-G
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_024334.3(TMEM43):āc.1112A>Gā(p.Tyr371Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,613,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y371H) has been classified as Likely benign.
Frequency
Consequence
NM_024334.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMEM43 | NM_024334.3 | c.1112A>G | p.Tyr371Cys | missense_variant | 12/12 | ENST00000306077.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMEM43 | ENST00000306077.5 | c.1112A>G | p.Tyr371Cys | missense_variant | 12/12 | 1 | NM_024334.3 | P1 | |
TMEM43 | ENST00000432444.2 | c.*1142A>G | 3_prime_UTR_variant, NMD_transcript_variant | 13/13 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152030Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251392Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135890
GnomAD4 exome AF: 0.0000410 AC: 60AN: 1461840Hom.: 0 Cov.: 32 AF XY: 0.0000426 AC XY: 31AN XY: 727222
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152030Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74256
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 5 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 371 of the TMEM43 protein (p.Tyr371Cys). This variant is present in population databases (rs752269639, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with TMEM43-related conditions. ClinVar contains an entry for this variant (Variation ID: 518601). 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 TMEM43 protein function with a positive predictive value of 80%. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | This missense variant replaces tyrosine with cysteine at codon 371 of the TMEM43 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 7/282768 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 16, 2023 | This missense variant replaces tyrosine with cysteine at codon 371 of the TMEM43 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 7/282768 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 30, 2016 | The p.Y371C variant (also known as c.1112A>G), located in coding exon 12 of the TMEM43 gene, results from an A to G substitution at nucleotide position 1112. The tyrosine at codon 371 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 02, 2024 | Variant summary: TMEM43 c.1112A>G (p.Tyr371Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 1613870 control chromosomes, predominantly at a frequency of 4.7e-05 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD (v4.0.0) database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in TMEM43 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (8.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1112A>G in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at