3-14132927-A-T

Position:

chr3-14132927-A-T

Variant summary

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

The NM_024334.3(TMEM43):c.504A>T(p.Lys168Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 1,612,400 control chromosomes in the GnomAD database, including 75,839 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 6766 hom., cov: 33)

Exomes 𝑓: 0.30 ( 69073 hom. )

Consequence

TMEM43
NM_024334.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.923

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=0.0023618042).

BP6

Variant 3-14132927-A-T is Benign according to our data. Variant chr3-14132927-A-T is described in ClinVar as [Benign]. Clinvar id is 46148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14132927-A-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.413 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.504A>T	p.Lys168Asn	missense_variant	6/12	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.504A>T	p.Lys168Asn	missense_variant	6/12	1	NM_024334.3	ENSP00000303992.5	Q9BTV4
TMEM43	ENST00000432444.2 linkuse as main transcript	n.*534A>T		non_coding_transcript_exon_variant	7/13	3		ENSP00000395617.1	F8WDL3
TMEM43	ENST00000432444.2 linkuse as main transcript	n.*534A>T		3_prime_UTR_variant	7/13	3		ENSP00000395617.1	F8WDL3

Frequencies

GnomAD3 genomes

AF:

0.295

AC:

44872

AN:

152002

Hom.:

6760

Cov.:

show subpopulations

Gnomad AFR

AF:

0.280

Gnomad AMI

AF:

0.239

Gnomad AMR

AF:

0.327

Gnomad ASJ

AF:

0.237

Gnomad EAS

AF:

0.429

Gnomad SAS

AF:

0.385

Gnomad FIN

AF:

0.289

Gnomad MID

AF:

0.244

Gnomad NFE

AF:

0.286

Gnomad OTH

AF:

0.294

GnomAD3 exomes

AF:

0.325

AC:

81669

AN:

251364

Hom.:

13981

AF XY:

0.321

AC XY:

43669

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.284

Gnomad AMR exome

AF:

0.420

Gnomad ASJ exome

AF:

0.249

Gnomad EAS exome

AF:

0.440

Gnomad SAS exome

AF:

0.372

Gnomad FIN exome

AF:

0.301

Gnomad NFE exome

AF:

0.283

Gnomad OTH exome

AF:

0.295

GnomAD4 exome

AF:

0.304

AC:

444009

AN:

1460280

Hom.:

69073

Cov.:

AF XY:

0.304

AC XY:

220957

AN XY:

726536

show subpopulations

Gnomad4 AFR exome

AF:

0.284

Gnomad4 AMR exome

AF:

0.412

Gnomad4 ASJ exome

AF:

0.242

Gnomad4 EAS exome

AF:

0.384

Gnomad4 SAS exome

AF:

0.369

Gnomad4 FIN exome

AF:

0.296

Gnomad4 NFE exome

AF:

0.295

Gnomad4 OTH exome

AF:

0.302

GnomAD4 genome

AF:

0.295

AC:

44911

AN:

152120

Hom.:

6766

Cov.:

AF XY:

0.297

AC XY:

22099

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.280

Gnomad4 AMR

AF:

0.328

Gnomad4 ASJ

AF:

0.237

Gnomad4 EAS

AF:

0.428

Gnomad4 SAS

AF:

0.385

Gnomad4 FIN

AF:

0.289

Gnomad4 NFE

AF:

0.286

Gnomad4 OTH

AF:

0.293

Alfa

AF:

0.291

Hom.:

5033

Bravo

AF:

0.300

TwinsUK

AF:

0.300

AC:

1113

ALSPAC

AF:

0.307

AC:

1182

ESP6500AA

AF:

0.287

AC:

1265

ESP6500EA

AF:

0.288

AC:

2475

ExAC

AF:

0.321

AC:

38951

Asia WGS

AF:

0.415

AC:

1436

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:12

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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 11, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 31, 2020	- -
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	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2008	- -

Arrhythmogenic right ventricular dysplasia 5

Benign:3

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	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Cardiomyopathy

Benign:2

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

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

Mar 11, 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

0.62

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0052

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0024

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.0

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.92

REVEL

Benign

0.039

Sift

Benign

0.22

Sift4G

Benign

0.28

Polyphen

0.20

Vest4

0.19

MutPred

0.13

Loss of ubiquitination at K168 (P = 0.0077);

MPC

0.13

ClinPred

0.013

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.088

gMVP

0.45

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