18-34755992-G-C

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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G6A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DTNA NM_001386795.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95

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	UniProt
DTNA	NM_001386795.1	c.16G>C	p.Gly6Arg	missense_variant	2/23	ENST00000444659.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DTNA	ENST00000444659.6	c.16G>C	p.Gly6Arg	missense_variant	2/23	5	NM_001386795.1	P3
	ENST00000596954.1	n.314-357C>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461004 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726860

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.: 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

Invitae

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	D
BayesDel_noAF	Uncertain	0.090
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;.;D;D;D;D;.;D;D;D;.
M_CAP	Benign	0.029	D
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	T
MutationAssessor	Benign	1.9	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	Pathogenic	0.88	D
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	D
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.

Other links and lift over

hg19: chr18-32335956;