rs35924492

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024334.3(TMEM43):c.698A>G(p.Tyr233Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00111 in 1,614,180 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Y233Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0060 ( 5 hom., cov: 33)

Exomes 𝑓: 0.00060 ( 15 hom. )

Consequence

TMEM43
NM_024334.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 4.43

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

arrhythmogenic right ventricular dysplasia 5
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
autosomal dominant Emery-Dreifuss muscular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
auditory neuropathy, autosomal dominant 3
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
Emery-Dreifuss muscular dystrophy 7, autosomal dominant
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

TMEM43 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013732225).

BP6

Variant 3-14134884-A-G is Benign according to our data. Variant chr3-14134884-A-G is described in ClinVar as Benign. ClinVar VariationId is 177840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00598 (911/152330) while in subpopulation AFR AF = 0.0211 (878/41584). AF 95% confidence interval is 0.02. There are 5 homozygotes in GnomAd4. There are 430 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 911 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM43	NM_024334.3 link	c.698A>G	p.Tyr233Cys	missense_variant	Exon 8 of 12	ENST00000306077.5	NP_077310.1	Q9BTV4A0A024R2F9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMEM43	ENST00000306077.5 link	c.698A>G	p.Tyr233Cys	missense_variant	Exon 8 of 12	1	NM_024334.3	ENSP00000303992.5	Q9BTV4
TMEM43	ENST00000432444.2 link	n.*728A>G		non_coding_transcript_exon_variant	Exon 9 of 13	3		ENSP00000395617.1	F8WDL3
TMEM43	ENST00000713947.1 link	n.334A>G		non_coding_transcript_exon_variant	Exon 2 of 6
TMEM43	ENST00000432444.2 link	n.*728A>G		3_prime_UTR_variant	Exon 9 of 13	3		ENSP00000395617.1	F8WDL3

Frequencies

GnomAD3 genomes

AF:

0.00597

AC:

909

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0211

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00155

AC:

390

AN:

251330

AF XY:

0.00106

show subpopulations

Gnomad AFR exome

AF:

0.0219

Gnomad AMR exome

AF:

0.000839

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000601

AC:

879

AN:

1461850

Hom.:

Cov.:

AF XY:

0.000523

AC XY:

380

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.0219

AC:

733

AN:

33480

American (AMR)

AF:

0.00101

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000207

AC:

AN:

1112000

Other (OTH)

AF:

0.00108

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

107

161

214

268

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00598

AC:

911

AN:

152330

Hom.:

Cov.:

AF XY:

0.00577

AC XY:

430

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0211

AC:

878

AN:

41584

American (AMR)

AF:

0.00144

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68020

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

144

192

240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00213

Hom.:

Bravo

AF:

0.00694

ESP6500AA

AF:

0.0252

AC:

111

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00204

AC:

248

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 05, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:4

Aug 11, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Tyr233Cys in exon 8 of TMEM43: This variant is not expected to have clinical sig nificance because it has been identified in 2.5% (111/4406) of African American chromosomes from by the NHLBI Exome Sequencing Project (http://evs.gs.washington .edu/EVS/rs35924492). -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:3

Mar 19, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 26, 2016

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 23, 2022

Cohesion Phenomics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Benign:1

Jul 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Arrhythmogenic right ventricular dysplasia 5

Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Oct 20, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Sudden cardiac arrest

Benign:1

Mar 15, 2019

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.019

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.7

PhyloP100

4.4

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.3

REVEL

Benign

0.090

Sift

Benign

0.15

Sift4G

Uncertain

0.045

Polyphen

0.99

Vest4

0.60

MVP

0.58

MPC

0.33

ClinPred

0.050

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.058

gMVP

0.38

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over