rs199526104

chr3-14139244-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PP3_Moderate BP6 BS1 BS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W316R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: TMEM43 NM_024334.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:3
• Conservation: PhyloP100: 9.29

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]

ACMG classification

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: {Uncertain_significance=7, Likely_benign=2, 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 GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM43	NM_024334.3	c.947G>C	p.Trp316Ser	missense_variant	11/12	ENST00000306077.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM43	ENST00000306077.5	c.947G>C	p.Trp316Ser	missense_variant	11/12	1	NM_024334.3	P1
TMEM43	ENST00000432444.2	c.*977G>C		3_prime_UTR_variant, NMD_transcript_variant	12/13	3

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152242 Hom.: 0 Cov.: 33

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: 43 AN: 251442 Hom.: 0 AF XY: 0.000206 AC XY: 28 AN XY: 135896

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.: 1 Cov.: 31 AF XY: 0.000149 AC XY: 108 AN XY: 727242

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: 5 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74366

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.: 0

Bravo AF: 0.0000869

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000436

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 05, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	TMEM43: BS1 -

not specified Uncertain:2

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. -
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 -

Arrhythmogenic right ventricular dysplasia 5 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	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	Dec 18, 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. -

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. -

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	T
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	32
Dann	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-8.5	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.89
MVP		0.71
MPC		0.51
ClinPred		0.83	D
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

Other links and lift over

dbSNP: rs199526104; hg19: chr3-14180744;