3-14135170-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP3_StrongBS2

The NM_024334.3(TMEM43):c.718C>G(p.Arg240Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,460,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R240C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

TMEM43
NM_024334.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.83

Publications

3 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:

ENSG00000268279 (HGNC:):

ENSG00000268279 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

BS2

High AC in GnomAdExome4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM43	NM_024334.3 link	c.718C>G	p.Arg240Gly	missense_variant	Exon 9 of 12	ENST00000306077.5	NP_077310.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM43	ENST00000306077.5 link	c.718C>G	p.Arg240Gly	missense_variant	Exon 9 of 12	1	NM_024334.3	ENSP00000303992.5
ENSG00000268279	ENST00000608606.1 link	n.-48C>G		upstream_gene_variant		5		ENSP00000476275.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000240

AC:

AN:

249912

AF XY:

0.0000296

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1460132

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

726480

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000193

AC:

AN:

51760

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000243

AC:

AN:

1111938

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.437

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 5

Uncertain:3

Dec 13, 2023

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with glycine at codon 240 of the TMEM43 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TMEM43-related disorders in the literature. This variant has been identified in 6/249912 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Jul 13, 2021

Clinical Genomics Laboratory, Stanford Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg240Gly variant in the TMEM43 gene has not been previously reported in association with disease.Different amino acid changes (p.Arg240Cys, p.Arg240His) have been previously reported at this residue; however, these variantsare of unknown significance(Andreasen et al., 2013; Verdonschot et al., 2020).This varianthas been identified in 6/249,912 chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The arginine at position 240is highly conserved. Computational tools predict that the p.Arg240Gly variant is deleterious; however, the accuracy of in silicoalgorithms is limited.These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of thep.Arg240Glyvariant is uncertain.Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: BP5; PM2; PP3] -

Aug 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TMEM43 protein function. ClinVar contains an entry for this variant (Variation ID: 1026428). This variant has not been reported in the literature in individuals affected with TMEM43-related conditions. This variant is present in population databases (rs367910936, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 240 of the TMEM43 protein (p.Arg240Gly). -

Cardiomyopathy

Uncertain:1

Sep 21, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

-0.097

MutationAssessor

Pathogenic

3.5

PhyloP100

1.8

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-6.5

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.96

MutPred

0.85

Loss of methylation at R240 (P = 0.0444);

MVP

0.62

MPC

0.45

ClinPred

0.97

GERP RS

5.0

Varity_R

0.94

gMVP

0.91

Mutation Taster

=12/88

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over