rs1553602940

Positions:

• chr3-14130862-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024334.3(TMEM43):​c.203T>C​(p.Leu68Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,490 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 (★). Synonymous variant affecting the same amino acid position (i.e. L68L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMEM43 NM_024334.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.29

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM43	NM_024334.3	c.203T>C	p.Leu68Pro	missense_variant	3/12	ENST00000306077.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM43	ENST00000306077.5	c.203T>C	p.Leu68Pro	missense_variant	3/12	1	NM_024334.3	P1
TMEM43	ENST00000432444.2	c.*233T>C		3_prime_UTR_variant, NMD_transcript_variant	4/13	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461490 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726988

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 29, 2017

This sequence change replaces leucine with proline at codon 68 of the TMEM43 protein (p.Leu68Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TMEM43-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.49	T
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.4	D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.054	T
Polyphen		1.0	D
Vest4		0.95
MutPred		0.60		Gain of disorder (P = 0.0067);
MVP		0.56
MPC		0.51
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.93
gMVP		0.92

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

Other links and lift over

dbSNP: rs1553602940; hg19: chr3-14172362;