rs747834756
Positions:
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_001386795.1(DTNA):c.869C>T(p.Thr290Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000353 in 1,613,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000037 ( 0 hom. )
Consequence
DTNA
NM_001386795.1 missense
NM_001386795.1 missense
Scores
3
10
5
Clinical Significance
Conservation
PhyloP100: 6.13
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 -6 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.21380466).
BS2
?
High AC in GnomAdExome4 at 54 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DTNA | NM_001386795.1 | c.869C>T | p.Thr290Met | missense_variant | 8/23 | ENST00000444659.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DTNA | ENST00000444659.6 | c.869C>T | p.Thr290Met | missense_variant | 8/23 | 5 | NM_001386795.1 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152124Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000478 AC: 12AN: 250888Hom.: 0 AF XY: 0.0000738 AC XY: 10AN XY: 135586
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GnomAD4 exome AF: 0.0000369 AC: 54AN: 1461482Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24AN XY: 727038
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152124Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74292
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Left ventricular noncompaction 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 28, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 22, 2022 | This variant has not been reported in the literature in individuals affected with DTNA-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 426774). This variant is present in population databases (rs747834756, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 290 of the DTNA protein (p.Thr290Met). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 16, 2024 | The c.869C>T (p.T290M) alteration is located in exon 8 (coding exon 7) of the DTNA gene. This alteration results from a C to T substitution at nucleotide position 869, causing the threonine (T) at amino acid position 290 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 05, 2017 | A variant of uncertain significance has been identified in the DTNA gene. Although the T290M variant has not been published as pathogenic or been reported as benign to our knowledge, it has been observed in 5/8264 (0.06%) alleles from individuals of East Asian ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T290M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position where amino acids with similar properties to threonine (T) are tolerated across species, although methionine (M) is tolerated at this position in one non-mammalian species. Nevertheless, in silico analysis predicts this variant is probably damaging to the protein structure/function. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;.;D;D;D;.;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;L;L;L;L;L;L;L;L;L;L;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;.;D;D;.;.;.;D;.;D;D;.
REVEL
Uncertain
Sift
Benign
D;D;.;D;D;.;.;.;D;.;D;D;.
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
P;P;.;.;.;.;B;P;P;.;P;P;.
Vest4
MutPred
Gain of MoRF binding (P = 0.0801);Gain of MoRF binding (P = 0.0801);Gain of MoRF binding (P = 0.0801);Gain of MoRF binding (P = 0.0801);Gain of MoRF binding (P = 0.0801);Gain of MoRF binding (P = 0.0801);Gain of MoRF binding (P = 0.0801);Gain of MoRF binding (P = 0.0801);Gain of MoRF binding (P = 0.0801);Gain of MoRF binding (P = 0.0801);Gain of MoRF binding (P = 0.0801);Gain of MoRF binding (P = 0.0801);.;
MVP
MPC
0.51
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
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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