chr3-14135170-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_024334.3(TMEM43):c.718C>T(p.Arg240Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000188 in 1,612,324 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. R240G) has been classified as Uncertain significance.
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.718C>T | p.Arg240Cys | missense_variant | 9/12 | ENST00000306077.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMEM43 | ENST00000306077.5 | c.718C>T | p.Arg240Cys | missense_variant | 9/12 | 1 | NM_024334.3 | P1 | |
TMEM43 | ENST00000432444.2 | c.*748C>T | 3_prime_UTR_variant, NMD_transcript_variant | 10/13 | 3 |
Frequencies
GnomAD3 genomes AF: 0.000118 AC: 18AN: 152194Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000176 AC: 44AN: 249912Hom.: 0 AF XY: 0.000207 AC XY: 28AN XY: 135196
GnomAD4 exome AF: 0.000195 AC: 285AN: 1460130Hom.: 0 Cov.: 32 AF XY: 0.000173 AC XY: 126AN XY: 726480
GnomAD4 genome AF: 0.000118 AC: 18AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74358
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 04, 2023 | This missense variant replaces arginine with cysteine at codon 240 of the TMEM43 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with arrhythmogenic right ventricular cardiomyopathy, who also carried a pathogenic deletion of exons 1-14 of the PKP2 gene (PMID: 21636032, 23178689, 25820315), which suggests that this missense variant was probably not the primary cause of disease in this individual. This variant has been identified in 48/281274 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 16, 2017 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 20, 2021 | Reported in one individual with ARVD/C who also harbors a deletion of exons 1-4 in the PKP2 gene (Kapplinger et al., 2011; Noorman et al., 2013; Groeneweg et al., 2015). Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 198154; Landrum et al., 2016) In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect This variant is associated with the following publications: (PMID: 28831623, 23178689, 23299917, 21636032, 25820315) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 15, 2022 | BP5 - |
Arrhythmogenic right ventricular dysplasia 5 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 240 of the TMEM43 protein (p.Arg240Cys). This variant is present in population databases (rs367910936, gnomAD 0.03%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular dysplasia/cardiomyopathy (PMID: 21636032, 25820315). ClinVar contains an entry for this variant (Variation ID: 202119). 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 | Feb 05, 2024 | This missense variant replaces arginine with cysteine at codon 240 of the TMEM43 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with arrhythmogenic right ventricular cardiomyopathy, who also carried a pathogenic deletion of exons 1-14 of the PKP2 gene (PMID: 21636032, 23178689, 25820315), which suggests that this missense variant was probably not the primary cause of disease in this individual. This variant has been identified in 48/281274 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 31, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 paper in HGMD; ExAC: 2/6110 Finnish chromosomes; ClinVar: 1 VUS - |
Arrhythmogenic right ventricular dysplasia 5;C3553060:Emery-Dreifuss muscular dystrophy 7, autosomal dominant;C5676964:Auditory neuropathy, autosomal dominant 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 09, 2021 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 12, 2022 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at