3-14129481-C-T

Variant summary

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

The NM_024334.3(TMEM43):c.82C>T(p.Arg28Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,614,114 control chromosomes in the GnomAD database, including 21 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. R28Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0052 ( 5 hom., cov: 31)

Exomes 𝑓: 0.0013 ( 16 hom. )

Consequence

TMEM43
NM_024334.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: 0.907

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=0.011812419).

BP6

Variant 3-14129481-C-T is Benign according to our data. Variant chr3-14129481-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 46153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14129481-C-T is described in Lovd as [Benign]. Variant chr3-14129481-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00523 (797/152254) while in subpopulation AFR AF= 0.0159 (661/41544). AF 95% confidence interval is 0.0149. There are 5 homozygotes in gnomad4. There are 374 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd at 792 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM43	NM_024334.3 linkuse as main transcript	c.82C>T	p.Arg28Trp	missense_variant	2/12	ENST00000306077.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM43	ENST00000306077.5 linkuse as main transcript	c.82C>T	p.Arg28Trp	missense_variant	2/12	1	NM_024334.3	P1
TMEM43	ENST00000432444.2 linkuse as main transcript	c.*112C>T		3_prime_UTR_variant, NMD_transcript_variant	3/13	3

Frequencies

GnomAD3 genomes

AF:

0.00521

AC:

792

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0158

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00258

AC:

648

AN:

251406

Hom.:

AF XY:

0.00235

AC XY:

320

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.0172

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.0123

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00314

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.000607

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00131

AC:

1908

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

995

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.0153

Gnomad4 AMR exome

AF:

0.00168

Gnomad4 ASJ exome

AF:

0.0114

Gnomad4 EAS exome

AF:

0.000378

Gnomad4 SAS exome

AF:

0.00356

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.000418

Gnomad4 OTH exome

AF:

0.00298

GnomAD4 genome

AF:

0.00523

AC:

797

AN:

152254

Hom.:

Cov.:

AF XY:

0.00502

AC XY:

374

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.0159

Gnomad4 AMR

AF:

0.00203

Gnomad4 ASJ

AF:

0.0115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000544

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00198

Hom.:

Bravo

AF:

0.00575

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0177

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.00289

AC:

351

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000981

EpiControl

AF:

0.000711

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 03, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 05, 2012	- -
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	GeneDx	Feb 28, 2012	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. -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	TMEM43: BS1, BS2 -

Cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 07, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Aug 04, 2017	- -

Arrhythmogenic right ventricular dysplasia 5

Benign:2

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

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 19, 2021

- -

Arrhythmogenic right ventricular cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 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

0.69

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.24

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.42

MutationAssessor

Pathogenic

3.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-4.2

REVEL

Uncertain

0.40

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.87

MVP

0.59

MPC

0.41

ClinPred

0.059

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.50

gMVP

0.85

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