rs397517387
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6
The NM_024334.3(TMEM43):āc.961A>Gā(p.Met321Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_024334.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMEM43 | NM_024334.3 | c.961A>G | p.Met321Val | missense_variant | 11/12 | ENST00000306077.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMEM43 | ENST00000306077.5 | c.961A>G | p.Met321Val | missense_variant | 11/12 | 1 | NM_024334.3 | P1 | |
TMEM43 | ENST00000432444.2 | c.*991A>G | 3_prime_UTR_variant, NMD_transcript_variant | 12/13 | 3 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461866Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727234
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74342
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 5 Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Mar 07, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 19, 2023 | This variant has not been reported in the literature in individuals affected with TMEM43-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 321 of the TMEM43 protein (p.Met321Val). ClinVar contains an entry for this variant (Variation ID: 46157). 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. 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 not expected to disrupt TMEM43 protein function. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 20, 2011 | Variant classified as Uncertain Significance - Favor Benign. The Met321Val varia nt has not been reported nor previously identified by our laboratory. Methionine (Met) at position 321 is not fully conserved in mammals, as opossum and more di stantly related species carry a valine (Val, this variant); this increases the l ikelihood that this change would be tolerated. Computational tools (AlignGVGD, P olyPhen2, SIFT) predict that a change to valine would not impact the protein, th ough the accuracy of these tools is unclear. Collectively, this data suggests th at the Met321Val variant may be benign, but additional information is needed to fully assess its clinical significance. - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 14, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at