chr3-49487663-A-G

Variant names:

• chr3-49487663-A-G
• rs9818590
• NM_004393.6:c.-117+17230A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004393.6(DAG1):​c.-117+17230A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 143,028 control chromosomes in the GnomAD database, including 6,986 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.31 (6986 hom., cov: 27)
• Consequence: DAG1 NM_004393.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.362
• Publications: 14 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 3-49487663-A-G is Benign according to our data. Variant chr3-49487663-A-G is described in ClinVar as [Benign]. Clinvar id is 1293349.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DAG1	NM_004393.6	c.-117+17230A>G		intron_variant	Intron 1 of 2	ENST00000308775.7	NP_004384.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DAG1	ENST00000308775.7	c.-117+17230A>G		intron_variant	Intron 1 of 2	1	NM_004393.6	ENSP00000312435.2

Frequencies

GnomAD3 genomes AF: 0.307 AC: 43943 AN: 142972 Hom.: 6978 Cov.: 27

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.201

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.471

Gnomad EAS AF: 0.0596

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.487

Gnomad MID AF: 0.330

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.309

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.307 AC: 43973 AN: 143028 Hom.: 6986 Cov.: 27 AF XY: 0.309 AC XY: 21425 AN XY: 69394

African (AFR) AF: 0.307 AC: 11808 AN: 38452

American (AMR) AF: 0.224 AC: 3175 AN: 14196

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 1598 AN: 3392

East Asian (EAS) AF: 0.0600 AC: 294 AN: 4904

South Asian (SAS) AF: 0.239 AC: 1072 AN: 4488

European-Finnish (FIN) AF: 0.487 AC: 4500 AN: 9244

Middle Eastern (MID) AF: 0.328 AC: 90 AN: 274

European-Non Finnish (NFE) AF: 0.317 AC: 20645 AN: 65202

Other (OTH) AF: 0.307 AC: 616 AN: 2004

Alfa AF: 0.288 Hom.: 855

Bravo AF: 0.277

Asia WGS AF: 0.148 AC: 522 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 01, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.5
DANN	Benign	0.82
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism (auto)

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: rs9818590; hg19: chr3-49525096;