rs150334659

Variant names:

• chr3-14129444-C-A
• rs150334659
• NM_024334.3:c.45C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-14129444-C-A
• chr3-14129444-C-G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_024334.3(TMEM43):​c.45C>A​(p.Val15Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,613,384 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V15V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00081 (1 hom., cov: 31)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: TMEM43 NM_024334.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0150
• 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: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), 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)

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 3-14129444-C-A is Benign according to our data. Variant chr3-14129444-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.015 with no splicing effect.
• BS2: High AC in GnomAd4 at 123 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM43	NM_024334.3	MANE Select	c.45C>A	p.Val15Val	synonymous	Exon 2 of 12	NP_077310.1	Q9BTV4
	TMEM43	NM_001407274.1		c.45C>A	p.Val15Val	synonymous	Exon 2 of 12	NP_001394203.1
	TMEM43	NM_001407275.1		c.45C>A	p.Val15Val	synonymous	Exon 2 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.45C>A	p.Val15Val	synonymous	Exon 2 of 12	ENSP00000303992.5	Q9BTV4
	TMEM43	ENST00000949127.1		c.45C>A	p.Val15Val	synonymous	Exon 2 of 12	ENSP00000619186.1
	TMEM43	ENST00000926410.1		c.45C>A	p.Val15Val	synonymous	Exon 2 of 12	ENSP00000596469.1

Frequencies

GnomAD3 genomes AF: 0.000805 AC: 122 AN: 151482 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00280

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000330

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000211 AC: 53 AN: 251424 AF XY: 0.000132

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000800 AC: 117 AN: 1461786 Hom.: 0 Cov.: 32 AF XY: 0.0000743 AC XY: 54 AN XY: 727200

African (AFR) AF: 0.00299 AC: 100 AN: 33476

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111936

Other (OTH) AF: 0.000166 AC: 10 AN: 60390

GnomAD4 genome AF: 0.000811 AC: 123 AN: 151598 Hom.: 1 Cov.: 31 AF XY: 0.000810 AC XY: 60 AN XY: 74034

African (AFR) AF: 0.00281 AC: 116 AN: 41256

American (AMR) AF: 0.000329 AC: 5 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67980

Other (OTH) AF: 0.000475 AC: 1 AN: 2104

Alfa AF: 0.000533 Hom.: 0

Bravo AF: 0.000752

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Arrhythmogenic right ventricular dysplasia 5 (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	3.8
DANN	Benign	0.80
PhyloP100		-0.015

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: rs150334659; hg19: chr3-14170944; COSMIC: COSV99853960; COSMIC: COSV99853960;