18-34755985-A-T

Position:

• chr18-34755985-A-T

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.61

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 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	c.9A>T	p.Glu3Asp	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.9A>T	p.Glu3Asp	missense_variant	2/23	5	NM_001386795.1	ENSP00000405819	P3
	ENST00000596954.1	n.314-350T>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460942 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726810

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.: 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

Jan 20, 2023

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. 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 glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 3 of the DTNA protein (p.Glu3Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
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	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;.;D;D;D;D;.;D;D;D;.
M_CAP	Benign	0.016	T
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	T
MutationAssessor	Benign	1.2	L;L;L;.;.;.;L;.;L;L;L;L;L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.75	T
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	D
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.

Other links and lift over

hg19: chr18-32335949;