NM_024334.3:c.486_489delCCGA

Variant names:

• chr3-14132905-TCGAC-T
• rs1060499910
• NM_024334.3:c.486_489delCCGA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024334.3(TMEM43):​c.486_489delCCGA​(p.Asp162GlufsTer44) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEM43 NM_024334.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.60
• Publications: 0 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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.486_489delCCGA	p.Asp162GlufsTer44	frameshift	Exon 6 of 12	NP_077310.1
	TMEM43	NM_001407274.1		c.489_492delCCGA	p.Asp163GlufsTer44	frameshift	Exon 6 of 12	NP_001394203.1
	TMEM43	NM_001407275.1		c.486_489delCCGA	p.Asp162GlufsTer44	frameshift	Exon 6 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.486_489delCCGA	p.Asp162GlufsTer44	frameshift	Exon 6 of 12	ENSP00000303992.5
	TMEM43	ENST00000432444.2	TSL:3	n.*516_*519delCCGA		non_coding_transcript_exon	Exon 7 of 13	ENSP00000395617.1
	TMEM43	ENST00000432444.2	TSL:3	n.*516_*519delCCGA		3_prime_UTR	Exon 7 of 13	ENSP00000395617.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

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
PhyloP100		9.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1060499910; hg19: chr3-14174405;