3-49488529-G-T

Variant names:

• chr3-49488529-G-T
• rs4855861
• NM_004393.6:c.-117+18096G>T

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+18096G>T 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 152,030 control chromosomes in the GnomAD database, including 14,890 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14890 hom., cov: 32)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: DAG1 NM_004393.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.59
• Publications: 4 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=-0.92).
• BP6: Variant 3-49488529-G-T is Benign according to our data. Variant chr3-49488529-G-T is described in ClinVar as [Benign]. Clinvar id is 1292613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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+18096G>T		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+18096G>T		intron_variant	Intron 1 of 2	1	NM_004393.6	ENSP00000312435.2

Frequencies

GnomAD3 genomes AF: 0.417 AC: 63377 AN: 151912 Hom.: 14880 Cov.: 32

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: 0.681

Gnomad FIN AF: 0.347

Gnomad MID AF: 0.385

Gnomad NFE AF: 0.427

Gnomad OTH AF: 0.421

GnomAD4 exome AF: 0.500 AC: 2 AN: 4 Hom.: 0 AF XY: 0.500 AC XY: 2 AN XY: 4

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) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 1 AN: 2

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.417 AC: 63404 AN: 152026 Hom.: 14890 Cov.: 32 AF XY: 0.423 AC XY: 31431 AN XY: 74298

African (AFR) AF: 0.271 AC: 11230 AN: 41464

American (AMR) AF: 0.572 AC: 8730 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 1188 AN: 3468

East Asian (EAS) AF: 0.930 AC: 4821 AN: 5184

South Asian (SAS) AF: 0.680 AC: 3272 AN: 4812

European-Finnish (FIN) AF: 0.347 AC: 3658 AN: 10550

Middle Eastern (MID) AF: 0.384 AC: 112 AN: 292

European-Non Finnish (NFE) AF: 0.427 AC: 29005 AN: 67978

Other (OTH) AF: 0.426 AC: 902 AN: 2116

Alfa AF: 0.417 Hom.: 1788

Bravo AF: 0.428

Asia WGS AF: 0.767 AC: 2659 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

- -

Jul 03, 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	-0.92
CADD	Benign	0.032
DANN	Benign	0.41
PhyloP100		-1.6
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: rs4855861; hg19: chr3-49525962;