rs1555778803

Positions:

• chr18-34766041-T-G

Variant summary

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

The NM_001386795.1(DTNA):​c.148T>G​(p.Leu50Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,330 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DTNA NM_001386795.1 missense, splice_region
• Scores: Splicing: ADA: 0.0001585
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.161

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]

ENSG00000268873 (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.148T>G	p.Leu50Val	missense_variant, splice_region_variant	3/23	ENST00000444659.6	NP_001373724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DTNA	ENST00000444659.6	c.148T>G	p.Leu50Val	missense_variant, splice_region_variant	3/23	5	NM_001386795.1	ENSP00000405819.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461330 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726964

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.: 32

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

Jun 20, 2019

This sequence change replaces leucine with valine at codon 50 of the DTNA protein (p.Leu50Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a DTNA-related disease. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.065	.;.;.;.;T;.;.;.;.;.;.;.;.;.;T;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;.
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.47	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.0	M;M;M;.;.;M;M;M;M;M;M;M;.;M;M;M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.7	N;.;N;.;.;.;N;N;.;.;.;N;.;.;N;N
REVEL	Benign	0.24
Sift	Benign	0.15	T;.;T;.;.;.;T;T;.;.;.;T;.;.;T;T
Sift4G	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.010	B;.;B;.;.;.;.;.;.;B;B;B;.;.;B;B
Vest4		0.75
MutPred		0.85		Gain of methylation at K47 (P = 0.0673);Gain of methylation at K47 (P = 0.0673);Gain of methylation at K47 (P = 0.0673);Gain of methylation at K47 (P = 0.0673);Gain of methylation at K47 (P = 0.0673);Gain of methylation at K47 (P = 0.0673);Gain of methylation at K47 (P = 0.0673);Gain of methylation at K47 (P = 0.0673);Gain of methylation at K47 (P = 0.0673);Gain of methylation at K47 (P = 0.0673);Gain of methylation at K47 (P = 0.0673);Gain of methylation at K47 (P = 0.0673);.;Gain of methylation at K47 (P = 0.0673);Gain of methylation at K47 (P = 0.0673);Gain of methylation at K47 (P = 0.0673);
MVP		0.66
MPC		0.34
ClinPred		0.20	T
GERP RS		0.17
Varity_R		0.12
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.020
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

LitVar

Other links and lift over

dbSNP: rs1555778803; hg19: chr18-32346005;