Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_001386795.1(DTNA):c.112G>A(p.Ala38Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A38A) has been classified as Likely benign.
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]
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP3
?
PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.97
Gain of phosphorylation at T34 (P = 0.0905);Gain of phosphorylation at T34 (P = 0.0905);Gain of phosphorylation at T34 (P = 0.0905);Gain of phosphorylation at T34 (P = 0.0905);Gain of phosphorylation at T34 (P = 0.0905);.;Gain of phosphorylation at T34 (P = 0.0905);Gain of phosphorylation at T34 (P = 0.0905);Gain of phosphorylation at T34 (P = 0.0905);Gain of phosphorylation at T34 (P = 0.0905);Gain of phosphorylation at T34 (P = 0.0905);Gain of phosphorylation at T34 (P = 0.0905);Gain of phosphorylation at T34 (P = 0.0905);Gain of phosphorylation at T34 (P = 0.0905);.;Gain of phosphorylation at T34 (P = 0.0905);Gain of phosphorylation at T34 (P = 0.0905);Gain of phosphorylation at T34 (P = 0.0905);