Variant rs751953774 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001386795.1(DTNA):c.435G>A(p.Met145Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,613,604 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

DTNA
NM_001386795.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.76

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DTNA	NM_001386795.1 linkuse as main transcript	c.435G>A	p.Met145Ile	missense_variant	5/23	ENST00000444659.6	NP_001373724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DTNA	ENST00000444659.6 linkuse as main transcript	c.435G>A	p.Met145Ile	missense_variant	5/23	5	NM_001386795.1	ENSP00000405819.2		Q9Y4J8-17A0A7P0TBH9

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251162

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461544

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152060

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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

Dec 04, 2015

The p.Met145Ile variant in DTNA has not been previously reported in individuals with cardiomyopathy, but has been identified in 1/65872 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs 751953774). Computational prediction tools and conservation analysis do not prov ide strong support for or against an impact to the protein. In summary, the clin ical significance of the p.Met145Ile variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

.;.;.;.;.;.;.;.;.;.;.;T;T

Eigen

Benign

0.058

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D;D;D;D;D;D;D;.;D;D;D;.

M_CAP

Benign

0.024

MetaRNN

Benign

0.38

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

0.97

L;L;L;L;L;L;L;L;L;L;L;L;L

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.0

N;.;N;.;N;N;.;.;.;N;.;N;N

REVEL

Benign

0.23

Sift

Benign

0.23

T;.;T;.;T;T;.;.;.;D;.;T;T

Sift4G

Uncertain

0.049

D;T;T;T;T;T;T;D;D;D;D;D;D

Polyphen

0.016

B;.;B;.;.;.;.;B;B;B;.;B;B

Vest4

0.49

MutPred

0.35

Gain of ubiquitination at K143 (P = 0.1079);Gain of ubiquitination at K143 (P = 0.1079);Gain of ubiquitination at K143 (P = 0.1079);Gain of ubiquitination at K143 (P = 0.1079);Gain of ubiquitination at K143 (P = 0.1079);Gain of ubiquitination at K143 (P = 0.1079);Gain of ubiquitination at K143 (P = 0.1079);Gain of ubiquitination at K143 (P = 0.1079);Gain of ubiquitination at K143 (P = 0.1079);Gain of ubiquitination at K143 (P = 0.1079);Gain of ubiquitination at K143 (P = 0.1079);Gain of ubiquitination at K143 (P = 0.1079);Gain of ubiquitination at K143 (P = 0.1079);

MVP

0.84

MPC

0.37

ClinPred

0.78

GERP RS

5.0

Varity_R

0.41

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.28

Position offset: 13

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over