rs138764471
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_024334.3(TMEM43):c.223G>A(p.Asp75Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_024334.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMEM43 | NM_024334.3 | c.223G>A | p.Asp75Asn | missense_variant | 3/12 | ENST00000306077.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMEM43 | ENST00000306077.5 | c.223G>A | p.Asp75Asn | missense_variant | 3/12 | 1 | NM_024334.3 | P1 | |
TMEM43 | ENST00000432444.2 | c.*253G>A | 3_prime_UTR_variant, NMD_transcript_variant | 4/13 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251056Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135678
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461472Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726962
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74340
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 05, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 14, 2023 | Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. - |
Arrhythmogenic right ventricular dysplasia 5 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 15, 2023 | This missense variant replaces aspartic acid with asparagine at codon 75 of the TMEM43 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/251056 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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 | Invitae | Dec 30, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 75 of the TMEM43 protein (p.Asp75Asn). This variant is present in population databases (rs138764471, gnomAD 0.0009%). 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: 466415). 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 with a negative 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. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 14, 2019 | This missense variant replaces aspartic acid with asparagine at codon 75 of the TMEM43 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/251056 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at