chr3-49530842-G-A

Position:

chr3-49530842-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004393.6(DAG1):c.331G>A(p.Asp111Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000802 in 1,614,210 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00096 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00079 ( 3 hom. )

Consequence

DAG1
NM_004393.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:9

Conservation

PhyloP100: 4.22

Variant links:

Genes affected

DAG1 (HGNC:2666): (dystroglycan 1) This gene encodes dystroglycan, a central component of dystrophin-glycoprotein complex that links the extracellular matrix and the cytoskeleton in the skeletal muscle. The encoded preproprotein undergoes O- and N-glycosylation, and proteolytic processing to generate alpha and beta subunits. Certain mutations in this gene are known to cause distinct forms of muscular dystrophy. Alternative splicing results in multiple transcript variants, all encoding the same protein. [provided by RefSeq, Nov 2015]

DAG1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007886469).

BP6

Variant 3-49530842-G-A is Benign according to our data. Variant chr3-49530842-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 208541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49530842-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000958 (146/152326) while in subpopulation EAS AF= 0.0252 (131/5194). AF 95% confidence interval is 0.0217. There are 4 homozygotes in gnomad4. There are 94 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DAG1	NM_004393.6 link	c.331G>A	p.Asp111Asn	missense_variant	3/3	ENST00000308775.7	NP_004384.5	Q14118A0A024R2W4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DAG1	ENST00000308775.7 link	c.331G>A	p.Asp111Asn	missense_variant	3/3	1	NM_004393.6	ENSP00000312435.2		Q14118

Frequencies

GnomAD3 genomes

AF:

0.000972

AC:

148

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0252

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00216

AC:

543

AN:

251166

Hom.:

AF XY:

0.00199

AC XY:

270

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.0268

Gnomad SAS exome

AF:

0.000915

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.000786

AC:

1149

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000813

AC XY:

591

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.000727

Gnomad4 EAS exome

AF:

0.0238

Gnomad4 SAS exome

AF:

0.00104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000351

Gnomad4 OTH exome

AF:

0.000778

GnomAD4 genome

AF:

0.000958

AC:

146

AN:

152326

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.0252

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00121

Hom.:

Bravo

AF:

0.00134

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00199

AC:

242

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	DAG1: BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2018	This variant is associated with the following publications: (PMID: 25503980, 29036200, 31180159) -

Autosomal recessive limb-girdle muscular dystrophy type 2P

Pathogenic:1Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 20, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 13, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 22, 2015	- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9;C4511963:Autosomal recessive limb-girdle muscular dystrophy type 2P

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 24, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

DAG1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 19, 2019

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

Benign

0.089

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

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

Eigen

Benign

-0.029

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

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

MetaRNN

Benign

0.0079

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

MetaSVM

Uncertain

0.52

MutationAssessor

Benign

0.64

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

PrimateAI

Benign

0.38

PROVEAN

Benign

-2.1

N;N;N;N;N;N;D

REVEL

Pathogenic

0.78

Sift

Benign

0.28

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

Sift4G

Benign

0.53

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

Polyphen

0.16

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

Vest4

0.68

MVP

0.76

MPC

0.27

ClinPred

0.025

GERP RS

5.9

Varity_R

0.19

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

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

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