chr3-14132927-A-T

Variant names:

• chr3-14132927-A-T
• rs4685076
• NM_024334.3:c.504A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024334.3(TMEM43):​c.504A>T​(p.Lys168Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 1,612,400 control chromosomes in the GnomAD database, including 75,839 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K168E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.30 (6766 hom., cov: 33)
  • Exomes 𝑓: 0.30 (69073 hom.)
• Consequence: TMEM43 NM_024334.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 0.923
• Publications: 35 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023618042).
• BP6: Variant 3-14132927-A-T is Benign according to our data. Variant chr3-14132927-A-T is described in ClinVar as Benign. ClinVar VariationId is 46148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

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.504A>T	p.Lys168Asn	missense	Exon 6 of 12	NP_077310.1	Q9BTV4
	TMEM43	NM_001407274.1		c.507A>T	p.Lys169Asn	missense	Exon 6 of 12	NP_001394203.1
	TMEM43	NM_001407275.1		c.504A>T	p.Lys168Asn	missense	Exon 6 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.504A>T	p.Lys168Asn	missense	Exon 6 of 12	ENSP00000303992.5	Q9BTV4
	TMEM43	ENST00000949127.1		c.507A>T	p.Lys169Asn	missense	Exon 6 of 12	ENSP00000619186.1
	TMEM43	ENST00000926410.1		c.504A>T	p.Lys168Asn	missense	Exon 6 of 12	ENSP00000596469.1

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44872 AN: 152002 Hom.: 6760 Cov.: 33

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.239

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.429

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.286

Gnomad OTH AF: 0.294

GnomAD2 exomes AF: 0.325 AC: 81669 AN: 251364 AF XY: 0.321

Gnomad AFR exome AF: 0.284

Gnomad AMR exome AF: 0.420

Gnomad ASJ exome AF: 0.249

Gnomad EAS exome AF: 0.440

Gnomad FIN exome AF: 0.301

Gnomad NFE exome AF: 0.283

Gnomad OTH exome AF: 0.295

GnomAD4 exome AF: 0.304 AC: 444009 AN: 1460280 Hom.: 69073 Cov.: 34 AF XY: 0.304 AC XY: 220957 AN XY: 726536

African (AFR) AF: 0.284 AC: 9487 AN: 33442

American (AMR) AF: 0.412 AC: 18421 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 6312 AN: 26120

East Asian (EAS) AF: 0.384 AC: 15227 AN: 39674

South Asian (SAS) AF: 0.369 AC: 31805 AN: 86174

European-Finnish (FIN) AF: 0.296 AC: 15777 AN: 53354

Middle Eastern (MID) AF: 0.219 AC: 1264 AN: 5764

European-Non Finnish (NFE) AF: 0.295 AC: 327478 AN: 1110726

Other (OTH) AF: 0.302 AC: 18238 AN: 60324

GnomAD4 genome AF: 0.295 AC: 44911 AN: 152120 Hom.: 6766 Cov.: 33 AF XY: 0.297 AC XY: 22099 AN XY: 74366

African (AFR) AF: 0.280 AC: 11635 AN: 41494

American (AMR) AF: 0.328 AC: 5012 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 821 AN: 3468

East Asian (EAS) AF: 0.428 AC: 2205 AN: 5156

South Asian (SAS) AF: 0.385 AC: 1857 AN: 4820

European-Finnish (FIN) AF: 0.289 AC: 3064 AN: 10586

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.286 AC: 19411 AN: 67980

Other (OTH) AF: 0.293 AC: 618 AN: 2108

Alfa AF: 0.291 Hom.: 5033

Bravo AF: 0.300

TwinsUK AF: 0.300 AC: 1113

ALSPAC AF: 0.307 AC: 1182

ESP6500AA AF: 0.287 AC: 1265

ESP6500EA AF: 0.288 AC: 2475

ExAC AF: 0.321 AC: 38951

Asia WGS AF: 0.415 AC: 1436 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	12	not specified (12)
-	-	3	Arrhythmogenic right ventricular dysplasia 5 (3)
-	-	2	Cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Emery-Dreifuss muscular dystrophy 7, autosomal dominant (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0052	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.92
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.039
Sift	Benign	0.22	T
Sift4G	Benign	0.28	T
Polyphen		0.20	B
Vest4		0.19
MutPred		0.13		Loss of ubiquitination at K168 (P = 0.0077)
MPC		0.13
ClinPred		0.013	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.088
gMVP		0.45
Mutation Taster		=68/32	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: rs4685076; hg19: chr3-14174427; COSMIC: COSV60146051; COSMIC: COSV60146051;