rs774912781

Variant names:

• chr18-34794127-G-A
• rs774912781
• NM_001386795.1:c.239G>A

Your query was ambiguous. Multiple possible variants found:

• chr18-34794127-G-A
• chr18-34794127-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001386795.1(DTNA):​c.239G>A​(p.Arg80His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000768 in 1,613,974 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R80C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000079 (0 hom.)
• Consequence: DTNA NM_001386795.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 8.07
• Publications: 1 publications found

Genes affected

DTNA (HGNC:3057): (dystrobrevin alpha) The protein encoded by this gene belongs to the dystrobrevin subfamily of the dystrophin family. This protein is a component of the dystrophin-associated protein complex (DPC), which consists of dystrophin and several integral and peripheral membrane proteins, including dystroglycans, sarcoglycans, syntrophins and alpha- and beta-dystrobrevin. The DPC localizes to the sarcolemma and its disruption is associated with various forms of muscular dystrophy. Mutations in this gene are associated with left ventricular noncompaction with congenital heart defects. Multiple alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

DTNA Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• left ventricular noncompaction 1

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Meniere disease

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DTNA	NM_001386795.1	c.239G>A	p.Arg80His	missense_variant	Exon 4 of 23	ENST00000444659.6	NP_001373724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DTNA	ENST00000444659.6	c.239G>A	p.Arg80His	missense_variant	Exon 4 of 23	5	NM_001386795.1	ENSP00000405819.2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000557 AC: 14 AN: 251296 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000794 AC: 116 AN: 1461856 Hom.: 0 Cov.: 32 AF XY: 0.0000646 AC XY: 47 AN XY: 727226

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 AN: 44716

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

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000899 AC: 100 AN: 1111996

Other (OTH) AF: 0.000149 AC: 9 AN: 60396

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74314

African (AFR) AF: 0.0000241 AC: 1 AN: 41424

American (AMR) AF: 0.000131 AC: 2 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000741 AC: 9

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 05, 2018

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

p.Arg80His (c.239G>A) in exon 4 of the DTNA gene (NM_032978.6) Chromosome location 18:32374091 G / A Based on the information reviewed below, we classify this as a variant of uncertain significance (VUS)concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. According to the Invitae report, this variant has not been reported in the literature in association with disease. This is a conservative amino acid change, resulting in the replacement of a positively-charged Arginine with a positively-charged Histidine. Arginine at this location is highly conserved across ~100 vertebrate species for which we have data. However, Histidine is the default amino acid in at least one species. There are no Likely Pathogenic or Pathogenic variants currently listed in ClinVar within 10 amino acids to either side. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). This variant was reported in 17 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 2 "Other ancestry", 2 East-Asian, 10 non-Finnish European, 2 Latino (out of 17,196, MAF = 0.006%), and 1 African ancestry individual. Ovarall minor allele frequency (MAF) = 0.006%. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases -

Left ventricular noncompaction 1 Uncertain:1

Sep 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 80 of the DTNA protein (p.Arg80His). This variant is present in population databases (rs774912781, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DTNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 411865). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DTNA protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	.;.;.;.;T;.;.;.;.;.;.;.;.;.;D;D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;.
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.2	M;M;M;.;.;M;M;M;M;M;M;M;.;M;M;M
PhyloP100		8.1
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.0	D;.;D;.;.;.;D;D;.;.;.;D;.;.;D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.020	D;.;D;.;.;.;D;D;.;.;.;D;.;.;D;D
Sift4G	Uncertain	0.029	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.84	P;.;B;.;.;.;.;.;.;B;P;B;.;.;B;B
Vest4		0.63
MutPred		0.61		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);.;Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);
MVP		0.76
MPC		0.72
ClinPred		0.29	T
GERP RS		5.4
Varity_R		0.77
gMVP		0.68
Mutation Taster		=175/125	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs774912781; hg19: chr18-32374091;