rs36083134

Variant names:

• chr3-14141688-G-A
• rs36083134
• NM_024334.3:c.1096G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-14141688-G-A
• chr3-14141688-G-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024334.3(TMEM43):​c.1096G>A​(p.Ala366Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00104 in 1,614,190 control chromosomes in the GnomAD database, including 19 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A366V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0054 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00058 (10 hom.)
• Consequence: TMEM43 NM_024334.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 4.22
• Publications: 5 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 -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 17 uncertain in NM_024334.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.008789092).
• BP6: Variant 3-14141688-G-A is Benign according to our data. Variant chr3-14141688-G-A is described in ClinVar as Benign. ClinVar VariationId is 46138.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 = 0.00544 (829/152338) while in subpopulation AFR AF = 0.0187 (778/41568). AF 95% confidence interval is 0.0176. There are 9 homozygotes in GnomAd4. There are 401 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 829 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.1096G>A	p.Ala366Thr	missense	Exon 12 of 12	NP_077310.1	Q9BTV4
	TMEM43	NM_001407274.1		c.1099G>A	p.Ala367Thr	missense	Exon 12 of 12	NP_001394203.1
	TMEM43	NM_001407275.1		c.1093G>A	p.Ala365Thr	missense	Exon 12 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.1096G>A	p.Ala366Thr	missense	Exon 12 of 12	ENSP00000303992.5	Q9BTV4
	ENSG00000268279	ENST00000608606.1	TSL:5	n.235+2391G>A		intron	N/A	ENSP00000476275.1	V9GY05
	TMEM43	ENST00000949127.1		c.1099G>A	p.Ala367Thr	missense	Exon 12 of 12	ENSP00000619186.1

Frequencies

GnomAD3 genomes AF: 0.00545 AC: 829 AN: 152220 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

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: 0.0000294

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00139 AC: 349 AN: 251390 AF XY: 0.00107

Gnomad AFR exome AF: 0.0182

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000581 AC: 849 AN: 1461852 Hom.: 10 Cov.: 32 AF XY: 0.000517 AC XY: 376 AN XY: 727230

African (AFR) AF: 0.0195 AC: 653 AN: 33480

American (AMR) AF: 0.00119 AC: 53 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1112002

Other (OTH) AF: 0.00161 AC: 97 AN: 60396

GnomAD4 genome AF: 0.00544 AC: 829 AN: 152338 Hom.: 9 Cov.: 33 AF XY: 0.00538 AC XY: 401 AN XY: 74496

African (AFR) AF: 0.0187 AC: 778 AN: 41568

American (AMR) AF: 0.00274 AC: 42 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

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: 0.0000294 AC: 2 AN: 68042

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00212 Hom.: 3

Bravo AF: 0.00629

ESP6500AA AF: 0.0186 AC: 82

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00168 AC: 204

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	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
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0087	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		4.2
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.12
Sift	Benign	0.20	T
Sift4G	Benign	0.25	T
Polyphen		0.68	P
Vest4		0.29
MVP		0.31
MPC		0.17
ClinPred		0.012	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.088
gMVP		0.42
Mutation Taster		=58/42	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: rs36083134; hg19: chr3-14183188;