rs1555778803

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001386795.1(DTNA):c.148T>G(p.Leu50Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,330 control chromosomes in the GnomAD database, with no homozygous occurrence. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DTNA
NM_001386795.1 missense, splice_region

Scores

Splicing: ADA: 0.0001585

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.161

Publications

0 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:

ENSG00000268873 (HGNC:58208):

ENSG00000268873 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DTNA	NM_001386795.1 link	c.148T>G	p.Leu50Val	missense_variant, splice_region_variant	Exon 3 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.148T>G	p.Leu50Val	missense_variant, splice_region_variant	Exon 3 of 23	5	NM_001386795.1	ENSP00000405819.2		Q9Y4J8-17A0A7P0TBH9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461330

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726964

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111636

Other (OTH)

AF:

0.00

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Left ventricular noncompaction 1

Uncertain:1

Jun 20, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This sequence change replaces leucine with valine at codon 50 of the DTNA protein (p.Leu50Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a DTNA-related disease. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.025

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.065

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

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.56

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.95

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

M_CAP

Benign

0.025

MetaRNN

Uncertain

0.47

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

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.0

M;M;M;.;.;M;M;M;M;M;M;M;.;M;M;M

PhyloP100

0.16

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.7

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

REVEL

Benign

0.24

Sift

Benign

0.15

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

Sift4G

Benign

0.22

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

Polyphen

0.010

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

Vest4

0.75

MutPred

0.85

Gain of methylation at K47 (P = 0.0673);Gain of methylation at K47 (P = 0.0673);Gain of methylation at K47 (P = 0.0673);Gain of methylation at K47 (P = 0.0673);Gain of methylation at K47 (P = 0.0673);Gain of methylation at K47 (P = 0.0673);Gain of methylation at K47 (P = 0.0673);Gain of methylation at K47 (P = 0.0673);Gain of methylation at K47 (P = 0.0673);Gain of methylation at K47 (P = 0.0673);Gain of methylation at K47 (P = 0.0673);Gain of methylation at K47 (P = 0.0673);.;Gain of methylation at K47 (P = 0.0673);Gain of methylation at K47 (P = 0.0673);Gain of methylation at K47 (P = 0.0673);

MVP

0.66

MPC

0.34

ClinPred

0.20

GERP RS

0.17

Varity_R

0.12

gMVP

0.70

Mutation Taster

=264/36

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00016

dbscSNV1_RF

Benign

0.020

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over