rs113449357

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024334.3(TMEM43):c.934C>T(p.Arg312Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,614,114 control chromosomes in the GnomAD database, including 190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R312Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.010 ( 13 hom., cov: 33)

Exomes 𝑓: 0.013 ( 177 hom. )

Consequence

TMEM43
NM_024334.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: 1.62

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=0.015833825).

BP6

Variant 3-14139231-C-T is Benign according to our data. Variant chr3-14139231-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 36873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14139231-C-T is described in Lovd as [Benign]. Variant chr3-14139231-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0103 (1572/152314) while in subpopulation NFE AF= 0.013 (884/68028). AF 95% confidence interval is 0.0123. There are 13 homozygotes in gnomad4. There are 849 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High AC in GnomAd at 1574 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM43	NM_024334.3 linkuse as main transcript	c.934C>T	p.Arg312Trp	missense_variant	11/12	ENST00000306077.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM43	ENST00000306077.5 linkuse as main transcript	c.934C>T	p.Arg312Trp	missense_variant	11/12	1	NM_024334.3	P1
TMEM43	ENST00000432444.2 linkuse as main transcript	c.*964C>T		3_prime_UTR_variant, NMD_transcript_variant	12/13	3

Frequencies

GnomAD3 genomes

AF:

0.0103

AC:

1574

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00227

Gnomad AMI

AF:

0.0450

Gnomad AMR

AF:

0.00661

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0389

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0130

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00969

AC:

2436

AN:

251430

Hom.:

AF XY:

0.00985

AC XY:

1338

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.00246

Gnomad AMR exome

AF:

0.00338

Gnomad ASJ exome

AF:

0.000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00255

Gnomad FIN exome

AF:

0.0356

Gnomad NFE exome

AF:

0.0120

Gnomad OTH exome

AF:

0.00863

GnomAD4 exome

AF:

0.0128

AC:

18663

AN:

1461800

Hom.:

177

Cov.:

AF XY:

0.0125

AC XY:

9108

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.00191

Gnomad4 AMR exome

AF:

0.00351

Gnomad4 ASJ exome

AF:

0.00122

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00238

Gnomad4 FIN exome

AF:

0.0343

Gnomad4 NFE exome

AF:

0.0142

Gnomad4 OTH exome

AF:

0.00975

GnomAD4 genome

AF:

0.0103

AC:

1572

AN:

152314

Hom.:

Cov.:

AF XY:

0.0114

AC XY:

849

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00226

Gnomad4 AMR

AF:

0.00660

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.0389

Gnomad4 NFE

AF:

0.0130

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.0113

Hom.:

Bravo

AF:

0.00776

TwinsUK

AF:

0.0146

AC:

ALSPAC

AF:

0.0150

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0134

AC:

115

ExAC

AF:

0.00904

AC:

1098

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0105

EpiControl

AF:

0.0103

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Genetic Services Laboratory, University of Chicago	Nov 03, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 17, 2012	Arg312Trp in Exon 11 of TMEM43: This variant is not expected to have clinical si gnificance because it has been identified in 1.3% (93/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs113449357). -

not provided

Benign:6

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	TMEM43: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 03, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2018	This variant is associated with the following publications: (PMID: 23812740, 25333069, 23161701, 27153395, 26332594, 31402444, 32880476) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Cardiomyopathy

Benign:3

Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 15, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Aug 17, 2017	- -

Arrhythmogenic right ventricular dysplasia 5;C3553060:Emery-Dreifuss muscular dystrophy 7, autosomal dominant;C5676964:Auditory neuropathy, autosomal dominant 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 20, 2021

- -

Arrhythmogenic right ventricular cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

- -

Arrhythmogenic right ventricular dysplasia 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 06, 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

Pathogenic

0.87

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.020

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.40

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.016

MetaSVM

Uncertain

-0.19

MutationAssessor

Pathogenic

3.5

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-7.5

REVEL

Uncertain

0.59

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MVP

0.78

MPC

0.41

ClinPred

0.066

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.86

gMVP

0.96

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