rs773224617
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_024334.3(TMEM43):c.1114C>T(p.Arg372Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000929 in 1,614,076 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).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
TMEM43
NM_024334.3 stop_gained
NM_024334.3 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 4.43
Genes affected
TMEM43 (HGNC:28472): (transmembrane protein 43) This gene belongs to the TMEM43 family. Defects in this gene are the cause of familial arrhythmogenic right ventricular dysplasia type 5 (ARVD5), also known as arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5). Arrhythmogenic right ventricular dysplasia is an inherited disorder, often involving both ventricles, and is characterized by ventricular tachycardia, heart failure, sudden cardiac death, and fibrofatty replacement of cardiomyocytes. This gene contains a response element for PPAR gamma (an adipogenic transcription factor), which may explain the fibrofatty replacement of the myocardium, a characteristic pathological finding in ARVC. [provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BS2
?
High AC in GnomAdExome4 at 11 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMEM43 | NM_024334.3 | c.1114C>T | p.Arg372Ter | stop_gained | 12/12 | ENST00000306077.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMEM43 | ENST00000306077.5 | c.1114C>T | p.Arg372Ter | stop_gained | 12/12 | 1 | NM_024334.3 | P1 | |
TMEM43 | ENST00000432444.2 | c.*1144C>T | 3_prime_UTR_variant, NMD_transcript_variant | 13/13 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152224Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251418Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135902
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GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461852Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727224
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152224Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74364
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:7
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Auditory neuropathy, autosomal dominant 3 Pathogenic:3
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, University Hospital Schleswig-Holstein | Sep 22, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 34050020). The variant has been reported to be associated with TMEM43 related disorder (ClinVar ID: VCV000403555 / PMID: 34050020). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 13, 2023 | - - |
Arrhythmogenic right ventricular dysplasia 5 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 23, 2023 | This variant changes one nucleotide in exon 12 of the TMEM43 gene, creating a premature translation stop signal. This variant is expected to escape nonsense-mediated decay and be expressed as a truncation protein. A functional study has shown that this variant causes progressive hearing loss in knock-in mouse which does not show any sign of arrhythmogenic right ventricular cardiomyopathy in the electrocardiography (Jang et al. 2020, doi: https://doi.org/10.1101/2020.07.27.222323). This variant has been reported in two families affected with adult-onset autosomal dominant auditory neuropathy spectrum disorder. Affected carriers from these families did not display symptoms of either arrhythmia or any other heart abnormalities (Jang et al. 2020, doi: https://doi.org/10.1101/2020.07.27.222323). This variant has been identified in 2/251418 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant has been observed in multiple individuals affected with auditory neuropathy spectrum disorder, but the available evidence is insufficient to determine the role of this variant in cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance for cardiomyopathy. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | This sequence change creates a premature translational stop signal (p.Arg372*) in the TMEM43 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the TMEM43 protein. This variant is present in population databases (rs773224617, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with auditory neuropathy (PMID: 34050020). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 403555). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects TMEM43 function (PMID: 34050020). 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 16, 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: This is a stop variant in exon 12 of 12 in TMEM43. This variant has not been reported in affected individuals and is not present in ClinVar. It has a Max MAF of 0.001% in ExAC (1 allele) and 0.006% in gnomAD (1 allele). This variant is predicted to be pathogenic by prediction tools. - |
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 16, 2021 | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 02, 2023 | This variant changes one nucleotide in exon 12 of the TMEM43 gene, creating a premature translation stop signal in the last exon. This variant is expected to escape nonsense-mediated decay and be expressed as a truncation protein. A functional study using a knock-in mouse model has shown that this variant results in progressive hearing loss without signs of arrhythmogenic cardiomyopathy (PMID: 34050020). This variant has been reported in two families affected with adult-onset autosomal dominant auditory neuropathy spectrum disorder. Affected carriers from these families did not display symptoms of arrhythmia or other heart abnormalities (PMID: 34050020). This variant has been identified in 2/251418 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Sep 20, 2021 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 23, 2021 | The p.R372* variant (also known as c.1114C>T), located in coding exon 12 of the TMEM43 gene, results from a C to T substitution at nucleotide position 1114. This changes the amino acid from an arginine to a stop codon within coding exon 12. This alteration is expected to result in premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of TMEM43 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at