rs199526104

Positions:

chr3-14139244-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PP3_ModerateBP6BS1BS2

The NM_024334.3(TMEM43):c.947G>C(p.Trp316Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,614,118 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 1 hom. )

Consequence

TMEM43
NM_024334.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:3

Conservation

PhyloP100: 9.29

Variant links:

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]

TMEM43 links:

ENSG00000268279 (HGNC:):

ENSG00000268279 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.863

BP6

Variant 3-14139244-G-C is Benign according to our data. Variant chr3-14139244-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46155.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7, Benign=1}.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000136 (199/1461876) while in subpopulation MID AF= 0.00225 (13/5768). AF 95% confidence interval is 0.00133. There are 1 homozygotes in gnomad4_exome. There are 108 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM43	NM_024334.3 linkuse as main transcript	c.947G>C	p.Trp316Ser	missense_variant	11/12	ENST00000306077.5	NP_077310.1	Q9BTV4A0A024R2F9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM43	ENST00000306077.5 linkuse as main transcript	c.947G>C	p.Trp316Ser	missense_variant	11/12	1	NM_024334.3	ENSP00000303992.5		Q9BTV4
ENSG00000268279	ENST00000608606.1 linkuse as main transcript	n.182G>C		non_coding_transcript_exon_variant	3/5	5		ENSP00000476275.1		V9GY05

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000171

AC:

AN:

251442

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000359

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000255

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000136

AC:

199

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

108

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000359

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000124

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000166

Hom.:

Bravo

AF:

0.0000869

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000206

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TMEM43: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 05, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2022	Reported in two individuals from one family with ARVC (Adler et al., 2016) and in one individual with DCM (Verdonschot et al., 2020) in published literature; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32880476, 30847666, 26743238) -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 22, 2012	Variant classified as Uncertain Significance - Favor Pathogenic. The Trp316Ser v ariant (TMEM3) has not been reported in the literature but has been identified i n one individual with clinical features of ARVD/C by our laboratory. Computatio nal analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPh en2, and SIFT) suggest that the Trp316Ser variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In additi on, this variant has been identified in 0.01% (1/7020) of European American chro mosomes from a broad population by the NHLBI Exome Sequencing Project (http://ev s.gs.washington.edu/EVS/). In summary, although data supports that the Trp316Ser variant may be pathogenic, additional studies are needed to fully assess its cl inical significance -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 27, 2020	Variant summary: TMEM43 c.947G>C (p.Trp316Ser) 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 0.00017 in 251442 control chromosomes (gnomAD). The observed variant frequency is approximately 20-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 benign. W316S has been reported in the literature in 2 individuals from one family affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (Adler_2016). In addition, one ClinVar submitter reports internal data of the variant identified in one individual with clinical features of ARVD/C (SCV000063079.6). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. A co-occurrence with a pathogenic variant has been reported (LMNA c.949G>A , p.Glu317Lys; Internal testing). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Arrhythmogenic right ventricular dysplasia 5

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 316 of the TMEM43 protein (p.Trp316Ser). This variant is present in population databases (rs199526104, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of TMEM43-related conditions (PMID: 26743238, 32880476). ClinVar contains an entry for this variant (Variation ID: 46155). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 03, 2024	This missense variant replaces tryptophan with serine at codon 316 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 2 related individuals suspected of having arrhythmogenic cardiomyopathy (PMID: 26743238), and in an individual affected with dilated cardiomyopathy (PMID: 32880476). This variant has also been identified in 44/282844 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population suggests this variant may not be disease-causing, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

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

Jul 22, 2021

- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Feb 22, 2023

This missense variant replaces tryptophan with serine at codon 316 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 2 related individuals suspected of having arrhythmogenic cardiomyopathy (PMID: 26743238), and in an individual affected with dilated cardiomyopathy (PMID: 32880476). This variant has also been identified in 44/282844 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population suggests this variant may not be disease-causing, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

TMEM43-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 08, 2024

The TMEM43 c.947G>C variant is predicted to result in the amino acid substitution p.Trp316Ser. This variant was reported in an individual with dilated cardiomyopathy ( Supplemental table 4 Verdonschot et al 2020. PubMed ID: 32880476). This variant is reported in 0.036% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2023

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Uncertain

0.059

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.86

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.86

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.8

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-8.5

REVEL

Uncertain

0.53

Sift

Uncertain

0.011

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.89

MVP

0.71

MPC

0.51

ClinPred

0.83

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.86

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over