rs6797164

Variant names:

• chr3-49468866-C-T
• rs6797164
• ENST00000469139.2:c.-306C>T

Variant summary

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

The ENST00000469139.2(DAG1):​c.-306C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.976 in 151,002 control chromosomes in the GnomAD database, including 72,062 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 0.98 (72042 hom., cov: 25)
  • Exomes 𝑓: 1.0 (20 hom.)
• Consequence: DAG1 ENST00000469139.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0820
• Publications: 2 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=-1.03).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DAG1	NM_001177643.3	c.-306C>T		upstream_gene_variant			NP_001171114.2
DAG1	XM_047447546.1	c.-719C>T		upstream_gene_variant			XP_047303502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DAG1	ENST00000469139.2	c.-306C>T		5_prime_UTR_variant	Exon 1 of 3	4		ENSP00000501165.2

Frequencies

GnomAD3 genomes AF: 0.976 AC: 147253 AN: 150846 Hom.: 71988 Cov.: 25

Gnomad AFR AF: 0.916

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.992

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.986

GnomAD4 exome AF: 1.00 AC: 40 AN: 40 Hom.: 20 Cov.: 0 AF XY: 1.00 AC XY: 36 AN XY: 36

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 1.00 AC: 2 AN: 2

South Asian (SAS) AF: 1.00 AC: 4 AN: 4

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 1.00 AC: 30 AN: 30

Other (OTH) AF: 1.00 AC: 2 AN: 2

GnomAD4 genome AF: 0.976 AC: 147365 AN: 150962 Hom.: 72042 Cov.: 25 AF XY: 0.976 AC XY: 71877 AN XY: 73628

African (AFR) AF: 0.916 AC: 37545 AN: 40976

American (AMR) AF: 0.992 AC: 15041 AN: 15158

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3468 AN: 3468

East Asian (EAS) AF: 1.00 AC: 5120 AN: 5120

South Asian (SAS) AF: 0.999 AC: 4762 AN: 4766

European-Finnish (FIN) AF: 1.00 AC: 10248 AN: 10248

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 67913 AN: 67930

Other (OTH) AF: 0.987 AC: 2064 AN: 2092

Alfa AF: 0.984 Hom.: 9530

Bravo AF: 0.973

Asia WGS AF: 0.995 AC: 3461 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	-1.0
CADD	Benign	1.0
DANN	Benign	0.42
PhyloP100		-0.082
PromoterAI		0.019	Neutral
Mutation Taster		=300/0	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: rs6797164; hg19: chr3-49506299;