rs371706980

Variant names:

• chr3-14130816-TC-T
• rs371706980
• NM_024334.3:c.163-3delC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_024334.3(TMEM43):​c.163-3delC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,613,546 control chromosomes in the GnomAD database, including 68 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00094 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (65 hom.)
• Consequence: TMEM43 NM_024334.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.179
• 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: 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 -16 ACMG points.

• BP6: Variant 3-14130816-TC-T is Benign according to our data. Variant chr3-14130816-TC-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00094 (143/152186) while in subpopulation SAS AF = 0.0288 (139/4820). AF 95% confidence interval is 0.0249. There are 3 homozygotes in GnomAd4. There are 112 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 143 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.163-3delC		splice_region intron	N/A	NP_077310.1	Q9BTV4
	TMEM43	NM_001407274.1		c.163-3delC		splice_region intron	N/A	NP_001394203.1
	TMEM43	NM_001407275.1		c.163-3delC		splice_region intron	N/A	NP_001394204.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM43	ENST00000306077.5	TSL:1 MANE Select	c.163-5delC		splice_region intron	N/A	ENSP00000303992.5	Q9BTV4
	TMEM43	ENST00000949127.1		c.163-5delC		splice_region intron	N/A	ENSP00000619186.1
	TMEM43	ENST00000926410.1		c.163-5delC		splice_region intron	N/A	ENSP00000596469.1

Frequencies

GnomAD3 genomes AF: 0.000940 AC: 143 AN: 152068 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0288

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00370 AC: 929 AN: 251054 AF XY: 0.00490

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00182 AC: 2660 AN: 1461360 Hom.: 65 Cov.: 31 AF XY: 0.00262 AC XY: 1906 AN XY: 726912

African (AFR) AF: 0.0000597 AC: 2 AN: 33474

American (AMR) AF: 0.0000672 AC: 3 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0292 AC: 2516 AN: 86140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111788

Other (OTH) AF: 0.00209 AC: 126 AN: 60360

GnomAD4 genome AF: 0.000940 AC: 143 AN: 152186 Hom.: 3 Cov.: 32 AF XY: 0.00151 AC XY: 112 AN XY: 74410

African (AFR) AF: 0.0000482 AC: 2 AN: 41520

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.0288 AC: 139 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000178

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	2	Cardiomyopathy (2)
-	-	1	Arrhythmogenic right ventricular dysplasia 5 (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.18
Mutation Taster		=99/1	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: rs371706980; hg19: chr3-14172316;