rs769969149

Variant names:

• chr3-14135829-G-A
• rs769969149
• NM_024334.3:c.803G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-14135829-G-A
• chr3-14135829-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_001407274.1(TMEM43):​c.806G>A​(p.Arg269Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. R269W) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TMEM43 NM_001407274.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 3.90
• Publications: 2 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22756615).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407274.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM43	NM_024334.3	MANE Select	c.803G>A	p.Arg268Gln	missense	Exon 10 of 12	NP_077310.1
	TMEM43	NM_001407274.1		c.806G>A	p.Arg269Gln	missense	Exon 10 of 12	NP_001394203.1
	TMEM43	NM_001407275.1		c.800G>A	p.Arg267Gln	missense	Exon 10 of 12	NP_001394204.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM43	ENST00000306077.5	TSL:1 MANE Select	c.803G>A	p.Arg268Gln	missense	Exon 10 of 12	ENSP00000303992.5
	ENSG00000268279	ENST00000608606.1	TSL:5	n.38G>A		non_coding_transcript_exon	Exon 2 of 5	ENSP00000476275.1
	TMEM43	ENST00000949127.1		c.806G>A	p.Arg269Gln	missense	Exon 10 of 12	ENSP00000619186.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249812 AF XY: 0.00000740

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: 0.00000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461310 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726958

African (AFR) AF: 0.0000299 AC: 1 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5332

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60348

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Arrhythmogenic right ventricular dysplasia 5 (2)
-	1	-	Cardiomyopathy (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0054	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.9
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.067
Sift	Benign	0.13	T
Sift4G	Benign	0.77	T
Polyphen		0.068	B
Vest4		0.36
MutPred		0.34		Loss of sheet (P = 0.0817)
MVP		0.46
MPC		0.11
ClinPred		0.47	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.059
gMVP		0.29
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs769969149; hg19: chr3-14177329;