NM_024334.3:c.512+19G>T

Variant names:

• chr3-14132954-G-T
• rs114026215
• NM_024334.3:c.512+19G>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.512+19G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.02 in 1,605,130 control chromosomes in the GnomAD database, including 408 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (30 hom., cov: 33)
  • Exomes 𝑓: 0.021 (378 hom.)
• Consequence: TMEM43 NM_024334.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.321
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, 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 (BayesDel_noAF=-0.84).
• BP6: Variant 3-14132954-G-T is Benign according to our data. Variant chr3-14132954-G-T is described in ClinVar as Benign. ClinVar VariationId is 261698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0144 (2189/152284) while in subpopulation NFE AF = 0.0233 (1582/68024). AF 95% confidence interval is 0.0223. There are 30 homozygotes in GnomAd4. There are 1040 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2189 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.512+19G>T		intron	N/A	NP_077310.1
	TMEM43	NM_001407274.1		c.515+19G>T		intron	N/A	NP_001394203.1
	TMEM43	NM_001407275.1		c.512+19G>T		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.512+19G>T		intron	N/A	ENSP00000303992.5
	TMEM43	ENST00000949127.1		c.515+19G>T		intron	N/A	ENSP00000619186.1
	TMEM43	ENST00000926410.1		c.512+19G>T		intron	N/A	ENSP00000596469.1

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2189 AN: 152166 Hom.: 30 Cov.: 33

Gnomad AFR AF: 0.00444

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00746

Gnomad FIN AF: 0.0105

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0233

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.0131 AC: 3286 AN: 251384 AF XY: 0.0136

Gnomad AFR exome AF: 0.00412

Gnomad AMR exome AF: 0.00772

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0115

Gnomad NFE exome AF: 0.0217

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.0206 AC: 29991 AN: 1452846 Hom.: 378 Cov.: 29 AF XY: 0.0201 AC XY: 14559 AN XY: 723364

African (AFR) AF: 0.00334 AC: 111 AN: 33270

American (AMR) AF: 0.00821 AC: 367 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.000882 AC: 23 AN: 26082

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39626

South Asian (SAS) AF: 0.00560 AC: 481 AN: 85954

European-Finnish (FIN) AF: 0.0104 AC: 556 AN: 53314

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5754

European-Non Finnish (NFE) AF: 0.0248 AC: 27410 AN: 1104072

Other (OTH) AF: 0.0170 AC: 1023 AN: 60076

GnomAD4 genome AF: 0.0144 AC: 2189 AN: 152284 Hom.: 30 Cov.: 33 AF XY: 0.0140 AC XY: 1040 AN XY: 74460

African (AFR) AF: 0.00443 AC: 184 AN: 41550

American (AMR) AF: 0.0160 AC: 245 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000866 AC: 3 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00746 AC: 36 AN: 4824

European-Finnish (FIN) AF: 0.0105 AC: 111 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0233 AC: 1582 AN: 68024

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.0190 Hom.: 60

Bravo AF: 0.0141

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	1	Arrhythmogenic right ventricular dysplasia 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.4
DANN	Benign	0.55
PhyloP100		-0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs114026215; hg19: chr3-14174454;