NM_024334.3:c.850C>G

Variant names:

• chr3-14135876-C-G
• rs727504764
• NM_024334.3:c.850C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024334.3(TMEM43):​c.850C>G​(p.Leu284Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L284L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEM43 NM_024334.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.83
• Publications: 1 publications found

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)

ENSG00000268279 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.412898).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024334.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM43	NM_024334.3	MANE Select	c.850C>G	p.Leu284Val	missense	Exon 10 of 12	NP_077310.1
	TMEM43	NM_001407274.1		c.853C>G	p.Leu285Val	missense	Exon 10 of 12	NP_001394203.1
	TMEM43	NM_001407275.1		c.847C>G	p.Leu283Val	missense	Exon 10 of 12	NP_001394204.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM43	ENST00000306077.5	TSL:1 MANE Select	c.850C>G	p.Leu284Val	missense	Exon 10 of 12	ENSP00000303992.5
	ENSG00000268279	ENST00000608606.1	TSL:5	n.85C>G		non_coding_transcript_exon	Exon 2 of 5	ENSP00000476275.1
	TMEM43	ENST00000949127.1		c.853C>G	p.Leu285Val	missense	Exon 10 of 12	ENSP00000619186.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Arrhythmogenic right ventricular dysplasia 5 (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0080	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.8
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.063
Sift	Benign	0.12	T
Sift4G	Benign	0.15	T
Polyphen		0.60	P
Vest4		0.42
MutPred		0.71		Loss of disorder (P = 0.2122)
MVP		0.22
MPC		0.19
ClinPred		0.75	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.040
gMVP		0.35
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs727504764; hg19: chr3-14177376;