Variant rs397514044 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024334.3(TMEM43):c.253G>A(p.Glu85Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,234 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TMEM43
NM_024334.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 4.92

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM43	NM_024334.3 linkuse as main transcript	c.253G>A	p.Glu85Lys	missense_variant	3/12	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.253G>A	p.Glu85Lys	missense_variant	3/12	1	NM_024334.3	ENSP00000303992.5	Q9BTV4
TMEM43	ENST00000432444.2 linkuse as main transcript	n.*283G>A		non_coding_transcript_exon_variant	4/13	3		ENSP00000395617.1	F8WDL3
TMEM43	ENST00000432444.2 linkuse as main transcript	n.*283G>A		3_prime_UTR_variant	4/13	3		ENSP00000395617.1	F8WDL3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250700

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135468

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461234

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726798

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 7, autosomal dominant

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2011

- -

Arrhythmogenic right ventricular dysplasia 5

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jul 29, 2024

This missense variant replaces glutamic acid with lysine at codon 85 of the TMEM43 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. An vitro functional study using transfected HeLa cells has shown that variant causes disrupted oligomerization of nuclear envelope protein LUMA (PMID: 21391237). This variant has been reported in individuals affected with Emery-Dreifuss muscular dystrophy (PMID: 21391237, 30311943). This variant has been identified in 1/250700 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

-0.0022

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.056

Eigen

Benign

0.080

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.012

MetaRNN

Uncertain

0.48

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.5

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-2.2

REVEL

Benign

0.079

Sift

Benign

0.065

Sift4G

Uncertain

0.059

Polyphen

0.12

Vest4

0.71

MutPred

0.41

Gain of methylation at E85 (P = 0.0148);

MVP

0.49

MPC

0.096

ClinPred

0.67

GERP RS

5.2

Varity_R

0.19

gMVP

0.87

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