chr3-49486803-T-G

Variant names:

• chr3-49486803-T-G
• rs3924462
• NM_004393.6:c.-117+16370T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004393.6(DAG1):​c.-117+16370T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.417 in 152,096 control chromosomes in the GnomAD database, including 14,879 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.42 (14879 hom., cov: 33)
• Consequence: DAG1 NM_004393.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.72
• Publications: 15 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.908 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DAG1	NM_004393.6	c.-117+16370T>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+16370T>G		intron_variant	Intron 1 of 2	1	NM_004393.6	ENSP00000312435.2

Frequencies

GnomAD3 genomes AF: 0.417 AC: 63375 AN: 151978 Hom.: 14869 Cov.: 33

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.533

Gnomad AMR AF: 0.572

Gnomad ASJ AF: 0.343

Gnomad EAS AF: 0.930

Gnomad SAS AF: 0.680

Gnomad FIN AF: 0.346

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.427

Gnomad OTH AF: 0.421

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

GnomAD4 genome AF: 0.417 AC: 63402 AN: 152096 Hom.: 14879 Cov.: 33 AF XY: 0.423 AC XY: 31436 AN XY: 74360

African (AFR) AF: 0.270 AC: 11219 AN: 41496

American (AMR) AF: 0.573 AC: 8748 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 1191 AN: 3472

East Asian (EAS) AF: 0.930 AC: 4815 AN: 5176

South Asian (SAS) AF: 0.679 AC: 3275 AN: 4822

European-Finnish (FIN) AF: 0.346 AC: 3661 AN: 10578

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.427 AC: 28993 AN: 67954

Other (OTH) AF: 0.426 AC: 900 AN: 2112

Alfa AF: 0.414 Hom.: 5165

Bravo AF: 0.428

Asia WGS AF: 0.767 AC: 2659 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.76
DANN	Benign	0.36
PhyloP100		-1.7
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: rs3924462; hg19: chr3-49524236;