NM_004393.6:c.-117+18434C>T

Variant names:

• chr3-49488867-C-T
• rs4855859
• NM_004393.6:c.-117+18434C>T

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+18434C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 151,398 control chromosomes in the GnomAD database, including 14,865 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.42 (14865 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DAG1 NM_004393.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.934
• Publications: 8 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=-1.0).
• BP6: Variant 3-49488867-C-T is Benign according to our data. Variant chr3-49488867-C-T is described in ClinVar as Benign. ClinVar VariationId is 1251824.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.908 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+18434C>T		intron	N/A	NP_004384.5	Q14118
	DAG1	NM_001165928.4		c.-268+122C>T		intron	N/A	NP_001159400.3	Q14118
	DAG1	NM_001177634.3		c.-117+1452C>T		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+18434C>T		intron	N/A	ENSP00000312435.2	Q14118
	DAG1	ENST00000418588.6	TSL:3	c.-117+11967C>T		intron	N/A	ENSP00000405859.2	Q14118
	DAG1	ENST00000421560.6	TSL:4	c.-117+18593C>T		intron	N/A	ENSP00000412067.2	Q14118

Frequencies

GnomAD3 genomes AF: 0.418 AC: 63270 AN: 151278 Hom.: 14855 Cov.: 31

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.535

Gnomad AMR AF: 0.572

Gnomad ASJ AF: 0.344

Gnomad EAS AF: 0.930

Gnomad SAS AF: 0.681

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.427

Gnomad OTH AF: 0.421

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 4 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

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: 0.00 AC: 0 AN: 4

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.418 AC: 63298 AN: 151398 Hom.: 14865 Cov.: 31 AF XY: 0.424 AC XY: 31369 AN XY: 73958

African (AFR) AF: 0.272 AC: 11205 AN: 41258

American (AMR) AF: 0.573 AC: 8705 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 1191 AN: 3466

East Asian (EAS) AF: 0.930 AC: 4809 AN: 5170

South Asian (SAS) AF: 0.680 AC: 3267 AN: 4804

European-Finnish (FIN) AF: 0.351 AC: 3640 AN: 10376

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

European-Non Finnish (NFE) AF: 0.427 AC: 28983 AN: 67816

Other (OTH) AF: 0.427 AC: 900 AN: 2110

Alfa AF: 0.412 Hom.: 2218

Bravo AF: 0.428

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	-1.0
CADD	Benign	0.21
DANN	Benign	0.49
PhyloP100		-0.93
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: rs4855859; hg19: chr3-49526300;