Variant chr18-34755992-G-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001386795.1(DTNA):c.16G>C(p.Gly6Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,004 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

DTNA
NM_001386795.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.95

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:

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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/exons	MANE	Protein	UniProt
DTNA	NM_001386795.1 link	c.16G>C	p.Gly6Arg	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 link	c.16G>C	p.Gly6Arg	missense_variant	2/23	5	NM_001386795.1	ENSP00000405819.2		Q9Y4J8-17A0A7P0TBH9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461004

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726860

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:

0.00000270

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 6 of the DTNA protein (p.Gly6Arg). 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 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

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.070

.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;D;D

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

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

M_CAP

Benign

0.029

MetaRNN

Uncertain

0.59

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.9

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

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.4

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

REVEL

Uncertain

0.31

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0020

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

Polyphen

1.0

D;.;P;.;.;.;.;.;.;.;.;D;D;D;.;D;D

Vest4

0.83

MutPred

0.34

Gain of MoRF binding (P = 0.0183);Gain of MoRF binding (P = 0.0183);Gain of MoRF binding (P = 0.0183);Gain of MoRF binding (P = 0.0183);Gain of MoRF binding (P = 0.0183);Gain of MoRF binding (P = 0.0183);Gain of MoRF binding (P = 0.0183);Gain of MoRF binding (P = 0.0183);Gain of MoRF binding (P = 0.0183);Gain of MoRF binding (P = 0.0183);Gain of MoRF binding (P = 0.0183);Gain of MoRF binding (P = 0.0183);Gain of MoRF binding (P = 0.0183);Gain of MoRF binding (P = 0.0183);Gain of MoRF binding (P = 0.0183);Gain of MoRF binding (P = 0.0183);Gain of MoRF binding (P = 0.0183);

MVP

0.57

MPC

0.61

ClinPred

0.98

GERP RS

5.8

Varity_R

0.68

gMVP

0.73

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

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