rs140768365
Positions:
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_001386795.1(DTNA):āc.316C>Gā(p.Gln106Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,614,176 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.00024 ( 1 hom., cov: 32)
Exomes š: 0.00021 ( 0 hom. )
Consequence
DTNA
NM_001386795.1 missense
NM_001386795.1 missense
Scores
2
5
12
Clinical Significance
Conservation
PhyloP100: 7.87
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.20172662).
BS2
High AC in GnomAd4 at 36 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DTNA | NM_001386795.1 | c.316C>G | p.Gln106Glu | missense_variant | 4/23 | ENST00000444659.6 | NP_001373724.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DTNA | ENST00000444659.6 | c.316C>G | p.Gln106Glu | missense_variant | 4/23 | 5 | NM_001386795.1 | ENSP00000405819 | P3 |
Frequencies
GnomAD3 genomes AF: 0.000237 AC: 36AN: 152220Hom.: 1 Cov.: 32
GnomAD3 genomes
AF:
AC:
36
AN:
152220
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000203 AC: 51AN: 251328Hom.: 0 AF XY: 0.000199 AC XY: 27AN XY: 135832
GnomAD3 exomes
AF:
AC:
51
AN:
251328
Hom.:
AF XY:
AC XY:
27
AN XY:
135832
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000209 AC: 305AN: 1461838Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 137AN XY: 727226
GnomAD4 exome
AF:
AC:
305
AN:
1461838
Hom.:
Cov.:
32
AF XY:
AC XY:
137
AN XY:
727226
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.000236 AC: 36AN: 152338Hom.: 1 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74492
GnomAD4 genome
AF:
AC:
36
AN:
152338
Hom.:
Cov.:
32
AF XY:
AC XY:
14
AN XY:
74492
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
0
ALSPAC
AF:
AC:
1
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
2
ExAC
AF:
AC:
31
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 31, 2023 | The c.316C>G (p.Q106E) alteration is located in exon 4 (coding exon 3) of the DTNA gene. This alteration results from a C to G substitution at nucleotide position 316, causing the glutamine (Q) at amino acid position 106 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 10, 2014 | The Gln106Glu variant in DTNA has not been previously reported in individuals wi th cardiomyopathy, but has been identified in 2/8600 European American chromosom es by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbS NP rs140768365). Computational prediction tools do not provide strong support fo r or against an impact to the protein. In summary, the clinical significance of the Gln106Glu variant is uncertain. - |
See cases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations | Nov 18, 2020 | We observed the c.316C>G (p.Q106E) genetic variant in a 57-y.o. male proband diagnosed with left ventricular non-compaction and dilated cardiomyopathy. The p.Q106E genetic variant is present in gnomAD database, its frequency is 2.051e-4. Online in silico tools predict genetic variant p.Q106E to be probably pathogenic. No functional studies are available to date; family DNA samples were likewise unavailable for segregation analysis, therefore, we could only classify the p.Q106E genetic variant as a variant of uncertain clinical significance. - |
Left ventricular noncompaction 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 24, 2024 | This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 106 of the DTNA protein (p.Gln106Glu). This variant is present in population databases (rs140768365, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with DTNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 178033). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DTNA protein function with a negative predictive value of 80%. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;.;.;.;T;.;.;.;.;.;.;.;.;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;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;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;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
Uncertain
T
PROVEAN
Benign
N;.;N;.;.;.;N;N;.;.;.;N;.;N;N
REVEL
Benign
Sift
Benign
T;.;T;.;.;.;T;T;.;.;.;T;.;T;T
Sift4G
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
B;.;D;.;.;.;.;.;.;P;B;D;.;D;D
Vest4
MVP
MPC
0.51
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at