chr3-49510792-G-C

Position:

chr3-49510792-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_004393.6(DAG1):c.258G>C(p.Leu86Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00459 in 1,614,192 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0031 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0047 ( 22 hom. )

Consequence

DAG1
NM_004393.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 1.02

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:

DAG1 (HGNC:):

DAG1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010102391).

BP6

Variant 3-49510792-G-C is Benign according to our data. Variant chr3-49510792-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195220.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2, Benign=2}. Variant chr3-49510792-G-C is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DAG1	NM_004393.6 linkuse as main transcript	c.258G>C	p.Leu86Phe	missense_variant	2/3	ENST00000308775.7	NP_004384.5	Q14118A0A024R2W4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DAG1	ENST00000308775.7 linkuse as main transcript	c.258G>C	p.Leu86Phe	missense_variant	2/3	1	NM_004393.6	ENSP00000312435.2		Q14118

Frequencies

GnomAD3 genomes

AF:

0.00311

AC:

473

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00347

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00508

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00289

AC:

725

AN:

251042

Hom.:

AF XY:

0.00290

AC XY:

393

AN XY:

135660

show subpopulations

Gnomad AFR exome

AF:

0.000739

Gnomad AMR exome

AF:

0.00171

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00137

Gnomad FIN exome

AF:

0.00134

Gnomad NFE exome

AF:

0.00489

Gnomad OTH exome

AF:

0.00408

GnomAD4 exome

AF:

0.00474

AC:

6932

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00467

AC XY:

3398

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00111

Gnomad4 AMR exome

AF:

0.00206

Gnomad4 ASJ exome

AF:

0.000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00168

Gnomad4 FIN exome

AF:

0.00187

Gnomad4 NFE exome

AF:

0.00559

Gnomad4 OTH exome

AF:

0.00477

GnomAD4 genome

AF:

0.00310

AC:

472

AN:

152320

Hom.:

Cov.:

AF XY:

0.00293

AC XY:

218

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00103

Gnomad4 AMR

AF:

0.00346

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.00507

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00449

Hom.:

Bravo

AF:

0.00341

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00442

AC:

ExAC

AF:

0.00287

AC:

348

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00409

EpiControl

AF:

0.00451

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	DAG1: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 2018	- -

not specified

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 05, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 26, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 27, 2023	- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

DAG1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 18, 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

0.095

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.36

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

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.73

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

M_CAP

Benign

0.035

MetaRNN

Benign

0.0061

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

MetaSVM

Uncertain

0.32

MutationAssessor

Benign

1.0

L;.;L;L;L;L;L;.;.;.;.

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.56

N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.23

Sift

Benign

0.24

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

Sift4G

Benign

0.15

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

Polyphen

0.0010

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

Vest4

0.15

MutPred

0.72

Loss of glycosylation at S90 (P = 0.03);Loss of glycosylation at S90 (P = 0.03);Loss of glycosylation at S90 (P = 0.03);Loss of glycosylation at S90 (P = 0.03);Loss of glycosylation at S90 (P = 0.03);Loss of glycosylation at S90 (P = 0.03);Loss of glycosylation at S90 (P = 0.03);Loss of glycosylation at S90 (P = 0.03);Loss of glycosylation at S90 (P = 0.03);Loss of glycosylation at S90 (P = 0.03);Loss of glycosylation at S90 (P = 0.03);

MVP

0.60

MPC

0.30

ClinPred

0.0050

GERP RS

4.3

Varity_R

0.038

gMVP

0.51

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