NM_004393.6:c.-117+18092T>C

Variant names:

• chr3-49488525-T-C
• rs11719996
• NM_004393.6:c.-117+18092T>C

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+18092T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.286 in 152,008 control chromosomes in the GnomAD database, including 6,745 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.29 (6744 hom., cov: 31)
  • Exomes 𝑓: 0.50 (1 hom.)
• Consequence: DAG1 NM_004393.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.580
• Publications: 13 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: Orphanet, Genomics England PanelApp, G2P
• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• neuromuscular disease caused by qualitative or quantitative defects of alpha-dystroglycan

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• 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=-0.93).
• BP6: Variant 3-49488525-T-C is Benign according to our data. Variant chr3-49488525-T-C is described in ClinVar as Benign. ClinVar VariationId is 1223881.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004393.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DAG1	NM_004393.6	MANE Select	c.-117+18092T>C		intron	N/A	NP_004384.5	Q14118
	DAG1	NM_001165928.4		c.-315-173T>C		intron	N/A	NP_001159400.3	Q14118
	DAG1	NM_001177634.3		c.-117+1110T>C		intron	N/A	NP_001171105.2	Q14118

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DAG1	ENST00000308775.7	TSL:1 MANE Select	c.-117+18092T>C		intron	N/A	ENSP00000312435.2	Q14118
	DAG1	ENST00000966350.1		c.-337T>C		5_prime_UTR	Exon 1 of 3	ENSP00000636409.1
	DAG1	ENST00000418588.6	TSL:3	c.-117+11625T>C		intron	N/A	ENSP00000405859.2	Q14118

Frequencies

GnomAD3 genomes AF: 0.286 AC: 43501 AN: 151884 Hom.: 6737 Cov.: 31

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.0588

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.472

Gnomad MID AF: 0.308

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.292

GnomAD4 exome AF: 0.500 AC: 4 AN: 8 Hom.: 1 AF XY: 0.667 AC XY: 4 AN XY: 6

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: 3 AN: 6

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

GnomAD4 genome AF: 0.286 AC: 43526 AN: 152000 Hom.: 6744 Cov.: 31 AF XY: 0.289 AC XY: 21489 AN XY: 74296

African (AFR) AF: 0.257 AC: 10664 AN: 41452

American (AMR) AF: 0.216 AC: 3302 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1601 AN: 3472

East Asian (EAS) AF: 0.0591 AC: 306 AN: 5174

South Asian (SAS) AF: 0.225 AC: 1084 AN: 4820

European-Finnish (FIN) AF: 0.472 AC: 4984 AN: 10552

Middle Eastern (MID) AF: 0.308 AC: 90 AN: 292

European-Non Finnish (NFE) AF: 0.305 AC: 20703 AN: 67962

Other (OTH) AF: 0.289 AC: 612 AN: 2114

Alfa AF: 0.136 Hom.: 284

Bravo AF: 0.265

Asia WGS AF: 0.144 AC: 507 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.3
DANN	Benign	0.40
PhyloP100		-0.58
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: rs11719996; hg19: chr3-49525958;