18-34755980-A-G

Position:

• chr18-34755980-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001386795.1(DTNA):​c.4A>G​(p.Ile2Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DTNA NM_001386795.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.34

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3871091).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DTNA	NM_001386795.1	c.4A>G	p.Ile2Val	missense_variant	2/23	ENST00000444659.6	NP_001373724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DTNA	ENST00000444659.6	c.4A>G	p.Ile2Val	missense_variant	2/23	5	NM_001386795.1	ENSP00000405819	P3
	ENST00000596954.1	n.314-345T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460818 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726746

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Left ventricular noncompaction 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 25, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with DTNA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2 of the DTNA protein (p.Ile2Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.0027	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.012	.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;T;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;.;D;D;D;D;.;D;D;D;.
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.1	M;M;M;.;.;.;M;.;M;M;M;M;M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.43	N;.;N;.;.;.;.;.;N;N;.;.;.;N;.;N;N
REVEL	Benign	0.28
Sift	Uncertain	0.0050	D;.;D;.;.;.;.;.;D;D;.;.;.;D;.;D;D
Sift4G	Uncertain	0.027	D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D
Polyphen		0.99	D;.;D;.;.;.;.;.;.;.;.;P;D;D;.;P;P
Vest4		0.57
MutPred		0.079		Gain of MoRF binding (P = 0.1374);Gain of MoRF binding (P = 0.1374);Gain of MoRF binding (P = 0.1374);Gain of MoRF binding (P = 0.1374);Gain of MoRF binding (P = 0.1374);Gain of MoRF binding (P = 0.1374);Gain of MoRF binding (P = 0.1374);Gain of MoRF binding (P = 0.1374);Gain of MoRF binding (P = 0.1374);Gain of MoRF binding (P = 0.1374);Gain of MoRF binding (P = 0.1374);Gain of MoRF binding (P = 0.1374);Gain of MoRF binding (P = 0.1374);Gain of MoRF binding (P = 0.1374);Gain of MoRF binding (P = 0.1374);Gain of MoRF binding (P = 0.1374);Gain of MoRF binding (P = 0.1374);
MVP		0.46
MPC		0.41
ClinPred		0.86	D
GERP RS		5.8
Varity_R		0.18
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs984784834; hg19: chr18-32335944;