NM_024334.3:c.953C>T

Variant names:

• chr3-14139250-C-T
• rs11924644
• NM_024334.3:c.953C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024334.3(TMEM43):​c.953C>T​(p.Ala318Val) variant causes a missense change. The variant allele was found at a frequency of 0.00108 in 1,614,174 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00059 (13 hom.)
• Consequence: TMEM43 NM_024334.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 5.39
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009778649).
• BP6: Variant 3-14139250-C-T is Benign according to our data. Variant chr3-14139250-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00572 (871/152314) while in subpopulation AFR AF = 0.0201 (837/41560). AF 95% confidence interval is 0.019. There are 8 homozygotes in GnomAd4. There are 409 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 871 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.953C>T	p.Ala318Val	missense	Exon 11 of 12	NP_077310.1	Q9BTV4
	TMEM43	NM_001407274.1		c.956C>T	p.Ala319Val	missense	Exon 11 of 12	NP_001394203.1
	TMEM43	NM_001407275.1		c.950C>T	p.Ala317Val	missense	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.953C>T	p.Ala318Val	missense	Exon 11 of 12	ENSP00000303992.5	Q9BTV4
	ENSG00000268279	ENST00000608606.1	TSL:5	n.188C>T		non_coding_transcript_exon	Exon 3 of 5	ENSP00000476275.1	V9GY05
	TMEM43	ENST00000949127.1		c.956C>T	p.Ala319Val	missense	Exon 11 of 12	ENSP00000619186.1

Frequencies

GnomAD3 genomes AF: 0.00567 AC: 863 AN: 152196 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00144 AC: 361 AN: 251424 AF XY: 0.000979

Gnomad AFR exome AF: 0.0202

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000594 AC: 869 AN: 1461860 Hom.: 13 Cov.: 31 AF XY: 0.000510 AC XY: 371 AN XY: 727236

African (AFR) AF: 0.0217 AC: 727 AN: 33480

American (AMR) AF: 0.000894 AC: 40 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

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

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111984

Other (OTH) AF: 0.00118 AC: 71 AN: 60394

GnomAD4 genome AF: 0.00572 AC: 871 AN: 152314 Hom.: 8 Cov.: 33 AF XY: 0.00549 AC XY: 409 AN XY: 74476

African (AFR) AF: 0.0201 AC: 837 AN: 41560

American (AMR) AF: 0.00157 AC: 24 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68032

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00284 Hom.: 7

Bravo AF: 0.00677

ESP6500AA AF: 0.0236 AC: 104

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00185 AC: 225

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	3	Cardiomyopathy (3)
-	-	1	Arrhythmogenic right ventricular dysplasia 5 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Sudden cardiac arrest (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0061	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.052
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0098	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.96	L
PhyloP100		5.4
PrimateAI	Benign	0.42	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.12
Sift	Benign	0.69	T
Sift4G	Benign	0.15	T
Polyphen		0.27	B
Vest4		0.45
MVP		0.31
MPC		0.17
ClinPred		0.040	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.51
Mutation Taster		=87/13	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: rs11924644; hg19: chr3-14180750; COSMIC: COSV99045636; COSMIC: COSV99045636;