3-49487345-G-C

Variant names:

• chr3-49487345-G-C
• rs6783003
• NM_004393.6:c.-117+16912G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004393.6(DAG1):​c.-117+16912G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 152,236 control chromosomes in the GnomAD database, including 3,370 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3368 hom., cov: 32)
  • Exomes 𝑓: 0.38 (2 hom.)
• Consequence: DAG1 NM_004393.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.04
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 3-49487345-G-C is Benign according to our data. Variant chr3-49487345-G-C is described in ClinVar as [Benign]. Clinvar id is 1179379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DAG1	NM_004393.6	c.-117+16912G>C		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+16912G>C		intron_variant	Intron 1 of 2	1	NM_004393.6	ENSP00000312435.2

Frequencies

GnomAD3 genomes AF: 0.197 AC: 30013 AN: 152084 Hom.: 3366 Cov.: 32

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.00864

Gnomad SAS AF: 0.0849

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.223

GnomAD4 exome AF: 0.382 AC: 13 AN: 34 Hom.: 2 Cov.: 0 AF XY: 0.417 AC XY: 10 AN XY: 24

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 2 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.367 AC: 11 AN: 30

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.197 AC: 30025 AN: 152202 Hom.: 3368 Cov.: 32 AF XY: 0.191 AC XY: 14188 AN XY: 74410

African (AFR) AF: 0.129 AC: 5357 AN: 41540

American (AMR) AF: 0.175 AC: 2675 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 665 AN: 3472

East Asian (EAS) AF: 0.00847 AC: 44 AN: 5194

South Asian (SAS) AF: 0.0850 AC: 410 AN: 4824

European-Finnish (FIN) AF: 0.181 AC: 1917 AN: 10574

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.267 AC: 18164 AN: 68000

Other (OTH) AF: 0.220 AC: 465 AN: 2110

Alfa AF: 0.225 Hom.: 512

Bravo AF: 0.194

Asia WGS AF: 0.0550 AC: 193 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 02, 2018

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	-0.87
CADD	Benign	6.6
DANN	Benign	0.61
PhyloP100		1.0
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: rs6783003; hg19: chr3-49524778;