Genetic Variant NM_001386795.1:c.9A>T (chr18-34755985-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001386795.1(DTNA):c.9A>T(p.Glu3Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,460,942 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: 6.8e-7 ( 0 hom. )

Consequence

DTNA
NM_001386795.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.61

Variant links:

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 links:

ENSG00000268873 (HGNC:58208):

ENSG00000268873 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DTNA	NM_001386795.1 link	c.9A>T	p.Glu3Asp	missense_variant	Exon 2 of 23	ENST00000444659.6	NP_001373724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DTNA	ENST00000444659.6 link	c.9A>T	p.Glu3Asp	missense_variant	Exon 2 of 23	5	NM_001386795.1	ENSP00000405819.2		Q9Y4J8-17A0A7P0TBH9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1460942

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726810

show subpopulations

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Left ventricular noncompaction 1

Uncertain:1

Jan 20, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 3 of the DTNA protein (p.Glu3Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DTNA-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DTNA protein function. 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

Uncertain

0.39

BayesDel_addAF

Benign

-0.028

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.025

.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;T;T

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.89

D;D;D;D;D;D;D;.;D;D;D;D;.;D;D;D;.

M_CAP

Benign

0.016

MetaRNN

Benign

0.24

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

L;L;L;.;.;.;L;.;L;L;L;L;L;L;L;L;L

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.4

N;.;N;.;.;.;.;.;N;N;.;.;.;N;.;N;N

REVEL

Benign

0.13

Sift

Pathogenic

0.0

D;.;D;.;.;.;.;.;D;D;.;.;.;D;.;D;D

Sift4G

Benign

0.17

T;T;T;T;T;T;T;.;T;T;T;T;T;T;T;T;T

Polyphen

0.14

B;.;B;.;.;.;.;.;.;.;.;B;B;B;.;B;B

Vest4

0.45

MutPred

0.21

Gain of MoRF binding (P = 0.1116);Gain of MoRF binding (P = 0.1116);Gain of MoRF binding (P = 0.1116);Gain of MoRF binding (P = 0.1116);Gain of MoRF binding (P = 0.1116);Gain of MoRF binding (P = 0.1116);Gain of MoRF binding (P = 0.1116);Gain of MoRF binding (P = 0.1116);Gain of MoRF binding (P = 0.1116);Gain of MoRF binding (P = 0.1116);Gain of MoRF binding (P = 0.1116);Gain of MoRF binding (P = 0.1116);Gain of MoRF binding (P = 0.1116);Gain of MoRF binding (P = 0.1116);Gain of MoRF binding (P = 0.1116);Gain of MoRF binding (P = 0.1116);Gain of MoRF binding (P = 0.1116);

MVP

0.71

MPC

0.34

ClinPred

0.89

GERP RS

5.8

Varity_R

0.49

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.21

Position offset: -9

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over