3-49531744-G-A

Variant names:

• chr3-49531744-G-A
• rs145765079
• NM_004393.6:c.1233G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004393.6(DAG1):​c.1233G>A​(p.Val411Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,613,830 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (10 hom.)
• Consequence: DAG1 NM_004393.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.546
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy type 2P

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Orphanet
• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• isolated asymptomatic elevation of creatine phosphokinase

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 3-49531744-G-A is Benign according to our data. Variant chr3-49531744-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 196384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.546 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004393.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DAG1	NM_004393.6	MANE Select	c.1233G>A	p.Val411Val	synonymous	Exon 3 of 3	NP_004384.5
	DAG1	NM_001165928.4		c.1233G>A	p.Val411Val	synonymous	Exon 6 of 6	NP_001159400.3
	DAG1	NM_001177634.3		c.1233G>A	p.Val411Val	synonymous	Exon 6 of 6	NP_001171105.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DAG1	ENST00000308775.7	TSL:1 MANE Select	c.1233G>A	p.Val411Val	synonymous	Exon 3 of 3	ENSP00000312435.2
	DAG1	ENST00000418588.6	TSL:3	c.1233G>A	p.Val411Val	synonymous	Exon 4 of 4	ENSP00000405859.2
	DAG1	ENST00000421560.6	TSL:4	c.1233G>A	p.Val411Val	synonymous	Exon 3 of 3	ENSP00000412067.2

Frequencies

GnomAD3 genomes AF: 0.00249 AC: 378 AN: 151820 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000969

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.00578

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00231

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00396

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00222 AC: 559 AN: 251462 AF XY: 0.00235

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00506

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00302

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00334 AC: 4884 AN: 1461892 Hom.: 10 Cov.: 33 AF XY: 0.00338 AC XY: 2456 AN XY: 727248

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.00165 AC: 74 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00379 AC: 99 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00283 AC: 244 AN: 86256

European-Finnish (FIN) AF: 0.000431 AC: 23 AN: 53420

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.00377 AC: 4192 AN: 1112012

Other (OTH) AF: 0.00376 AC: 227 AN: 60396

GnomAD4 genome AF: 0.00249 AC: 378 AN: 151938 Hom.: 2 Cov.: 32 AF XY: 0.00234 AC XY: 174 AN XY: 74272

African (AFR) AF: 0.000966 AC: 40 AN: 41422

American (AMR) AF: 0.00184 AC: 28 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00578 AC: 20 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00231 AC: 11 AN: 4764

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10596

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00396 AC: 269 AN: 67964

Other (OTH) AF: 0.00332 AC: 7 AN: 2106

Alfa AF: 0.00323 Hom.: 2

Bravo AF: 0.00246

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00349

EpiControl AF: 0.00249

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Nov 14, 2018

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 26, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 20, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DAG1: BP4, BP7

Sep 03, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25671699)

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9;C4511963:Autosomal recessive limb-girdle muscular dystrophy type 2P Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DAG1-related disorder Benign:1

Dec 09, 2019

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	6.5
DANN	Benign	0.67
PhyloP100		0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs145765079; hg19: chr3-49569177;