rs35100587

Variant names:

• chr3-14139206-C-T
• rs35100587
• NM_024334.3:c.909C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_024334.3(TMEM43):​c.909C>T​(p.Ser303Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.02 in 1,613,800 control chromosomes in the GnomAD database, including 430 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (40 hom., cov: 33)
  • Exomes 𝑓: 0.020 (390 hom.)
• Consequence: TMEM43 NM_024334.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.592
• Publications: 6 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)

ENSG00000268279 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 3-14139206-C-T is Benign according to our data. Variant chr3-14139206-C-T is described in ClinVar as Benign. ClinVar VariationId is 46154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.592 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0203 (3093/152308) while in subpopulation SAS AF = 0.0332 (160/4824). AF 95% confidence interval is 0.029. There are 40 homozygotes in GnomAd4. There are 1483 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3093 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.909C>T	p.Ser303Ser	synonymous	Exon 11 of 12	NP_077310.1	Q9BTV4
	TMEM43	NM_001407274.1		c.912C>T	p.Ser304Ser	synonymous	Exon 11 of 12	NP_001394203.1
	TMEM43	NM_001407275.1		c.906C>T	p.Ser302Ser	synonymous	Exon 11 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.909C>T	p.Ser303Ser	synonymous	Exon 11 of 12	ENSP00000303992.5	Q9BTV4
	ENSG00000268279	ENST00000608606.1	TSL:5	n.144C>T		non_coding_transcript_exon	Exon 3 of 5	ENSP00000476275.1	V9GY05
	TMEM43	ENST00000949127.1		c.912C>T	p.Ser304Ser	synonymous	Exon 11 of 12	ENSP00000619186.1

Frequencies

GnomAD3 genomes AF: 0.0203 AC: 3086 AN: 152190 Hom.: 40 Cov.: 33

Gnomad AFR AF: 0.0294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0142

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0325

Gnomad FIN AF: 0.0116

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0188

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.0184 AC: 4637 AN: 251432 AF XY: 0.0190

Gnomad AFR exome AF: 0.0292

Gnomad AMR exome AF: 0.0104

Gnomad ASJ exome AF: 0.00575

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.0215

Gnomad OTH exome AF: 0.0186

GnomAD4 exome AF: 0.0199 AC: 29155 AN: 1461492 Hom.: 390 Cov.: 31 AF XY: 0.0204 AC XY: 14824 AN XY: 727058

African (AFR) AF: 0.0293 AC: 982 AN: 33468

American (AMR) AF: 0.0113 AC: 504 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00612 AC: 160 AN: 26128

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0306 AC: 2643 AN: 86242

European-Finnish (FIN) AF: 0.0137 AC: 733 AN: 53416

Middle Eastern (MID) AF: 0.0349 AC: 201 AN: 5766

European-Non Finnish (NFE) AF: 0.0205 AC: 22749 AN: 1111666

Other (OTH) AF: 0.0195 AC: 1179 AN: 60382

GnomAD4 genome AF: 0.0203 AC: 3093 AN: 152308 Hom.: 40 Cov.: 33 AF XY: 0.0199 AC XY: 1483 AN XY: 74468

African (AFR) AF: 0.0294 AC: 1222 AN: 41564

American (AMR) AF: 0.0142 AC: 217 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.0332 AC: 160 AN: 4824

European-Finnish (FIN) AF: 0.0116 AC: 123 AN: 10620

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0188 AC: 1281 AN: 68022

Other (OTH) AF: 0.0237 AC: 50 AN: 2114

Alfa AF: 0.0220 Hom.: 23

Bravo AF: 0.0206

Asia WGS AF: 0.0180 AC: 64 AN: 3478

EpiCase AF: 0.0219

EpiControl AF: 0.0231

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	2	Arrhythmogenic right ventricular dysplasia 5 (2)
-	-	2	Cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	12
DANN	Benign	0.70
PhyloP100		0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism (auto)

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: rs35100587; hg19: chr3-14180706; COSMIC: COSV107377746; COSMIC: COSV107377746;