rs727505085
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_001386795.1(DTNA):c.953C>A(p.Pro318His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,012 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 (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
DTNA
NM_001386795.1 missense
NM_001386795.1 missense
Scores
10
5
3
Clinical Significance
Conservation
PhyloP100: 7.90
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 Likely_benign. Variant got -3 ACMG points.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.773
BS2
?
High AC in GnomAdExome4 at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DTNA | NM_001386795.1 | c.953C>A | p.Pro318His | missense_variant | 9/23 | ENST00000444659.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DTNA | ENST00000444659.6 | c.953C>A | p.Pro318His | missense_variant | 9/23 | 5 | NM_001386795.1 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251434Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135882
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461864Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727232
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74306
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 16, 2014 | The Pro318His variant in DTNA has not been previously reported in individuals wi th cardiomyopathy or in large population studies. Computational prediction tool s and conservation analysis suggest that the Pro318His variant may impact the pr otein, though this information is not predictive enough to determine pathogenici ty. In summary, the clinical significance of the Pro318His variant is uncertain. - |
Left ventricular noncompaction 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Feb 24, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;.;D;D;D;.;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;M;M;M;M;M;M;M;M;M;M;M;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;.;D;D;.;.;.;D;.;D;D;.
REVEL
Uncertain
Sift
Uncertain
D;D;.;D;D;.;.;.;D;.;D;D;.
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
D;D;.;.;.;.;D;D;D;.;D;D;.
Vest4
MutPred
Loss of glycosylation at P318 (P = 0.0517);Loss of glycosylation at P318 (P = 0.0517);Loss of glycosylation at P318 (P = 0.0517);Loss of glycosylation at P318 (P = 0.0517);Loss of glycosylation at P318 (P = 0.0517);Loss of glycosylation at P318 (P = 0.0517);Loss of glycosylation at P318 (P = 0.0517);Loss of glycosylation at P318 (P = 0.0517);Loss of glycosylation at P318 (P = 0.0517);Loss of glycosylation at P318 (P = 0.0517);Loss of glycosylation at P318 (P = 0.0517);Loss of glycosylation at P318 (P = 0.0517);.;
MVP
MPC
1.1
ClinPred
D
GERP RS
Varity_R
gMVP
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