rs148123045

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001386795.1(DTNA):c.1000G>A(p.Val334Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,613,666 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

DTNA
NM_001386795.1 missense, splice_region

Scores

Splicing: ADA: 0.9738

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 10.0

Publications

4 publications found

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]

DTNA Gene-Disease associations (from GenCC):

dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
left ventricular noncompaction 1
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
Meniere disease
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
congenital heart disease
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

DTNA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00822553).

BP6

Variant 18-34820914-G-A is Benign according to our data. Variant chr18-34820914-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46410.

BS2

High AC in GnomAd4 at 175 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DTNA	NM_001386795.1 link	c.1000G>A	p.Val334Met	missense_variant, splice_region_variant	Exon 9 of 23	ENST00000444659.6	NP_001373724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DTNA	ENST00000444659.6 link	c.1000G>A	p.Val334Met	missense_variant, splice_region_variant	Exon 9 of 23	5	NM_001386795.1	ENSP00000405819.2

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

173

AN:

151730

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00117

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00522

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000971

Gnomad OTH

AF:

0.000961

GnomAD2 exomes

AF:

0.000927

AC:

233

AN:

251432

AF XY:

0.000920

show subpopulations

Gnomad AFR exome

AF:

0.00166

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00480

Gnomad NFE exome

AF:

0.000739

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00109

AC:

1598

AN:

1461820

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

762

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.00212

AC:

AN:

33478

American (AMR)

AF:

0.000291

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00470

AC:

251

AN:

53416

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00109

AC:

1217

AN:

1111950

Other (OTH)

AF:

0.000695

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

181

272

362

453

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00115

AC:

175

AN:

151846

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

74210

show subpopulations

African (AFR)

AF:

0.00121

AC:

AN:

41288

American (AMR)

AF:

0.000131

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00522

AC:

AN:

10542

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000971

AC:

AN:

67984

Other (OTH)

AF:

0.000951

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00105

Hom.:

Bravo

AF:

0.000842

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000964

AC:

117

EpiCase

AF:

0.000818

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 02, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The variant c.1000G>A (p.Val334Ile) in DTNA gene involves a conserved nucleotide with 3/5 in silico programs predicting a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large and broad control population from ExAC with an allele frequency of 117/121378 (1/1037), which exceeds the estimated maximum expected allele frequency for a pathogenic DTNA variant of 1/40000. The variant of interest has been reported in individuals undergoing exome sequencing with limited information (i.e. information about co-occurrence and/or co-segregation data). In addition, multiple reputable clinical laboratories cite the variant with a classification of "uncertain significance," although it should be noted the classification evaluation occurred prior to the availablity of the ExAC dataset. Therefore, taken all available lines of evidence into consideration, the variant of interest is classified as Benign. -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

not specified

Uncertain:1Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 18, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Val334Ile varia nt in DTNA has been previously identified in one infant with HCM (LMM unpublishe d data). This variant is present at low frequency in various cohorts, the highes t being 0.16% (7/4406) in a broad African American cohort screened by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs148123045). Computational analyses (biochemical amino acid properties, conservation, AlignG VGD, PolyPhen2, and SIFT) suggest that the Val334Ile variant may not impact the protein, though this information is not predictive enough to rule out pathogenic ity. In summary, although these data support that the Val334Ile variant may be b enign, additional studies are needed to fully assess its clinical significance. -

Jun 28, 2017

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Left ventricular noncompaction 1

Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 28, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

DTNA-related disorder

Benign:1

Jun 28, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

.;.;.;.;T;T

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D;D;.;D;.

M_CAP

Benign

0.053

MetaRNN

Benign

0.0082

T;T;T;T;T;T

MetaSVM

Benign

-0.95

PhyloP100

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.67

N;N;.;.;N;N

REVEL

Benign

0.27

Sift

Benign

0.080

T;D;.;.;T;T

Sift4G

Benign

0.063

T;T;T;T;T;T

Polyphen

0.97

D;D;D;D;B;B

Vest4

0.49

MVP

0.59

ClinPred

0.060

GERP RS

5.7

PromoterAI

0.036

Neutral

(source)

Varity_R

0.084

Mutation Taster

=39/61

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Benign

0.64

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over