18-34838101-C-T
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_001386795.1(DTNA):c.1183C>T(p.Pro395Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,613,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000025 ( 0 hom. )
Consequence
DTNA
NM_001386795.1 missense
NM_001386795.1 missense
Scores
19
Clinical Significance
Conservation
PhyloP100: 3.63
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.060192168).
BS2
High AC in GnomAdExome4 at 37 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DTNA | NM_001386795.1 | c.1183C>T | p.Pro395Ser | missense_variant | 12/23 | ENST00000444659.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DTNA | ENST00000444659.6 | c.1183C>T | p.Pro395Ser | missense_variant | 12/23 | 5 | NM_001386795.1 | P3 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000558 AC: 14AN: 250962Hom.: 0 AF XY: 0.0000885 AC XY: 12AN XY: 135638
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GnomAD4 exome AF: 0.0000253 AC: 37AN: 1461478Hom.: 0 Cov.: 31 AF XY: 0.0000426 AC XY: 31AN XY: 727030
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152304Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74490
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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 | Invitae | Mar 08, 2021 | In summary, this variant is a rare 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. This variant is present in population databases (rs768198248, ExAC 0.04%) but has not been reported in the literature in individuals with a DTNA-related disease. This sequence change replaces proline with serine at codon 365 of the DTNA protein (p.Pro365Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
.;T;T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
D;D;.;T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;N;N;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N;.
REVEL
Benign
Sift
Benign
T;T;T;T;.
Sift4G
Benign
T;T;T;T;T
Polyphen
B;B;B;.;B
Vest4
MutPred
0.22
.;Loss of catalytic residue at P367 (P = 0.0149);Loss of catalytic residue at P367 (P = 0.0149);.;.;
MVP
ClinPred
T
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at