rs145765079

Positions:

• chr3-49531744-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004393.6(DAG1):​c.1233G>A​(p.Val411=) 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:7
• Conservation: PhyloP100: 0.546

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 196384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49531744-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.546 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DAG1	NM_004393.6	c.1233G>A	p.Val411=	synonymous_variant	3/3	ENST00000308775.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DAG1	ENST00000308775.7	c.1233G>A	p.Val411=	synonymous_variant	3/3	1	NM_004393.6	P1

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

GnomAD3 exomes AF: 0.00222 AC: 559 AN: 251462 Hom.: 1 AF XY: 0.00235 AC XY: 319 AN XY: 135906

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 SAS exome AF: 0.00255

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

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00379

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00283

Gnomad4 FIN exome AF: 0.000431

Gnomad4 NFE exome AF: 0.00377

Gnomad4 OTH exome AF: 0.00376

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

Gnomad4 AFR AF: 0.000966

Gnomad4 AMR AF: 0.00184

Gnomad4 ASJ AF: 0.00578

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00231

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00396

Gnomad4 OTH AF: 0.00332

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 12, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 03, 2020	This variant is associated with the following publications: (PMID: 25671699) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	DAG1: BP4, BP7, BS2 -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 14, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 26, 2015	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

DAG1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 09, 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
BayesDel_noAF	Benign	-0.62
CADD	Benign	6.5
DANN	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs145765079; hg19: chr3-49569177;