3-14125194-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PVS1_SupportingPM2BS2

The NM_024334.3(TMEM43):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,458,064 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

TMEM43
NM_024334.3 start_lost

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.03

Publications

0 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: Likely_benign. The variant received -1 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 36 codons. Genomic position: 14129505. Lost 0.088 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM43	NM_024334.3 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 12	ENST00000306077.5	NP_077310.1	Q9BTV4A0A024R2F9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM43	ENST00000306077.5 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 12	1	NM_024334.3	ENSP00000303992.5		Q9BTV4
TMEM43	ENST00000432444.2 link	n.1A>G		non_coding_transcript_exon_variant	Exon 1 of 13	3		ENSP00000395617.1		F8WDL3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000420

AC:

AN:

238152

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000931

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1458064

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725292

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44550

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26052

East Asian (EAS)

AF:

0.00

AC:

AN:

39616

South Asian (SAS)

AF:

0.00

AC:

AN:

85774

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51466

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111242

Other (OTH)

AF:

0.00

AC:

AN:

60160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000828

AC:

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;C3553060:Emery-Dreifuss muscular dystrophy 7, autosomal dominant;C5676964:Auditory neuropathy, autosomal dominant 3

Uncertain:2

Jun 12, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Sep 16, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Uncertain:1

Aug 10, 2016

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.M1? variant (also known as c.1A>G), located in coding exon 1 of the TMEM43 gene, results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. Based on data from ExAC, the G allele has an overall frequency of <0.01% (1/81382). This amino acid position is highly conserved in available vertebrate species. Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. There are alternate in-frame methionines 36 and 41 amino acids downstream from this initiation site which may result in an N-terminal truncation; however, direct evidence is unavailable. While the N-terminus of this protein is expected to be structurally important (Bengtsson L et al. J. Cell. Sci., 2008 Feb;121:536-48), its functional significance is not well established. Furthermore, loss of function of TMEM43 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Arrhythmogenic right ventricular dysplasia 5

Uncertain:1

Aug 15, 2023

All of Us Research Program, National Institutes of 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

BayesDel_addAF

Benign

-0.016

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.0085

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.27

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.73

MetaSVM

Benign

-1.0

PhyloP100

2.0

PROVEAN

Benign

-0.65

REVEL

Benign

0.28

Sift

Uncertain

0.020

Sift4G

Benign

0.41

Polyphen

0.32

Vest4

0.67

MutPred

0.64

Gain of catalytic residue at M1 (P = 0.0199);

MVP

0.19

ClinPred

0.77

GERP RS

3.6

PromoterAI

-0.31

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.45

gMVP

0.77

Mutation Taster

=25/175

disease causing

(source)

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

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3-14125194-A-G

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