rs140768365

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001386795.1(DTNA):ā€‹c.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

Scores

2
5
12

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.87
Variant links:
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
DTNANM_001386795.1 linkuse as main transcriptc.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
DTNAENST00000444659.6 linkuse as main transcriptc.316C>G p.Gln106Glu missense_variant 4/235 NM_001386795.1 ENSP00000405819 P3Q9Y4J8-17

Frequencies

GnomAD3 genomes
AF:
0.000237
AC:
36
AN:
152220
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000397
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000203
AC:
51
AN:
251328
Hom.:
0
AF XY:
0.000199
AC XY:
27
AN XY:
135832
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.0000993
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000422
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000209
AC:
305
AN:
1461838
Hom.:
0
Cov.:
32
AF XY:
0.000188
AC XY:
137
AN XY:
727226
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000749
Gnomad4 NFE exome
AF:
0.000260
Gnomad4 OTH exome
AF:
0.000132
GnomAD4 genome
AF:
0.000236
AC:
36
AN:
152338
Hom.:
1
Cov.:
32
AF XY:
0.000188
AC XY:
14
AN XY:
74492
show subpopulations
Gnomad4 AFR
AF:
0.000168
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000397
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000237
Hom.:
0
Bravo
AF:
0.000189
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000255
AC:
31
EpiCase
AF:
0.000273
EpiControl
AF:
0.000415

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 submitterclinical testingAmbry GeneticsMay 31, 2023The 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 submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJul 10, 2014The 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 submitterclinical testingPetrovsky National Research Centre of Surgery, The Federal Agency for Scientific OrganizationsNov 18, 2020We 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 24, 2024This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.070
T
BayesDel_noAF
Uncertain
-0.010
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.027
.;.;.;.;T;.;.;.;.;.;.;.;.;T;T
Eigen
Uncertain
0.44
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D;D;D;D;D;.;D;D;D;.
M_CAP
Benign
0.034
D
MetaRNN
Benign
0.20
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.57
T
MutationAssessor
Benign
1.3
L;L;L;.;.;L;L;L;L;L;L;L;L;L;L
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-1.8
N;.;N;.;.;.;N;N;.;.;.;N;.;N;N
REVEL
Benign
0.26
Sift
Benign
0.40
T;.;T;.;.;.;T;T;.;.;.;T;.;T;T
Sift4G
Benign
0.64
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.15
B;.;D;.;.;.;.;.;.;P;B;D;.;D;D
Vest4
0.74
MVP
0.83
MPC
0.51
ClinPred
0.15
T
GERP RS
5.4
Varity_R
0.61
gMVP
0.63

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs140768365; hg19: chr18-32374168; COSMIC: COSV99311863; COSMIC: COSV99311863; API