rs2340917

Positions:

chr3-14133762-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024334.3(TMEM43):c.536T>C(p.Met179Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,613,488 control chromosomes in the GnomAD database, including 92,444 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M179V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.36 ( 10310 hom., cov: 33)

Exomes 𝑓: 0.33 ( 82134 hom. )

Consequence

TMEM43
NM_024334.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:20

Conservation

PhyloP100: 3.13

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.0180454E-5).

BP6

Variant 3-14133762-T-C is Benign according to our data. Variant chr3-14133762-T-C is described in ClinVar as [Benign]. Clinvar id is 46150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14133762-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.629 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM43	NM_024334.3 linkuse as main transcript	c.536T>C	p.Met179Thr	missense_variant	7/12	ENST00000306077.5	NP_077310.1	Q9BTV4A0A024R2F9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TMEM43	ENST00000306077.5 linkuse as main transcript	c.536T>C	p.Met179Thr	missense_variant	7/12	1	NM_024334.3	ENSP00000303992.5	Q9BTV4
TMEM43	ENST00000432444.2 linkuse as main transcript	n.*566T>C		non_coding_transcript_exon_variant	8/13	3		ENSP00000395617.1	F8WDL3
TMEM43	ENST00000432444.2 linkuse as main transcript	n.*566T>C		3_prime_UTR_variant	8/13	3		ENSP00000395617.1	F8WDL3

Frequencies

GnomAD3 genomes

AF:

0.357

AC:

54173

AN:

151938

Hom.:

10300

Cov.:

show subpopulations

Gnomad AFR

AF:

0.415

Gnomad AMI

AF:

0.245

Gnomad AMR

AF:

0.435

Gnomad ASJ

AF:

0.241

Gnomad EAS

AF:

0.648

Gnomad SAS

AF:

0.433

Gnomad FIN

AF:

0.301

Gnomad MID

AF:

0.247

Gnomad NFE

AF:

0.293

Gnomad OTH

AF:

0.338

GnomAD3 exomes

AF:

0.379

AC:

95282

AN:

251456

Hom.:

20258

AF XY:

0.368

AC XY:

50070

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.417

Gnomad AMR exome

AF:

0.557

Gnomad ASJ exome

AF:

0.253

Gnomad EAS exome

AF:

0.670

Gnomad SAS exome

AF:

0.410

Gnomad FIN exome

AF:

0.314

Gnomad NFE exome

AF:

0.290

Gnomad OTH exome

AF:

0.333

GnomAD4 exome

AF:

0.326

AC:

476559

AN:

1461432

Hom.:

82134

Cov.:

AF XY:

0.326

AC XY:

236741

AN XY:

727038

show subpopulations

Gnomad4 AFR exome

AF:

0.421

Gnomad4 AMR exome

AF:

0.545

Gnomad4 ASJ exome

AF:

0.246

Gnomad4 EAS exome

AF:

0.601

Gnomad4 SAS exome

AF:

0.408

Gnomad4 FIN exome

AF:

0.309

Gnomad4 NFE exome

AF:

0.301

Gnomad4 OTH exome

AF:

0.336

GnomAD4 genome

AF:

0.357

AC:

54234

AN:

152056

Hom.:

10310

Cov.:

AF XY:

0.361

AC XY:

26815

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.416

Gnomad4 AMR

AF:

0.436

Gnomad4 ASJ

AF:

0.241

Gnomad4 EAS

AF:

0.648

Gnomad4 SAS

AF:

0.433

Gnomad4 FIN

AF:

0.301

Gnomad4 NFE

AF:

0.293

Gnomad4 OTH

AF:

0.339

Alfa

AF:

0.311

Hom.:

19348

Bravo

AF:

0.373

TwinsUK

AF:

0.306

AC:

1135

ALSPAC

AF:

0.311

AC:

1199

ESP6500AA

AF:

0.406

AC:

1787

ESP6500EA

AF:

0.295

AC:

2541

ExAC

AF:

0.372

AC:

45200

Asia WGS

AF:

0.553

AC:

1918

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:11

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 16, 2012	Met179Thr in exon 7 of TMEM43: This variant is not expected to have clinical sig nificance because it has been identified in 29.7% (2082/47020) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS/ dbSNP rs2340917). -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 12, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Arrhythmogenic right ventricular dysplasia 5

Benign:4

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

Cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 15, 2018	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -

Emery-Dreifuss muscular dystrophy 7, autosomal dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2015

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

Benign

0.045

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.19

DEOGEN2

Benign

0.0042

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.021

MetaRNN

Benign

0.000010

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-2.3

PrimateAI

Uncertain

0.50

PROVEAN

Benign

2.6

REVEL

Benign

0.12

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.051

MPC

0.076

ClinPred

0.0041

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.084

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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