NM_004393.6:c.-117+18178A>T

Variant names:

• chr3-49488611-A-T
• rs4855860
• NM_004393.6:c.-117+18178A>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+18178A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.903 in 150,356 control chromosomes in the GnomAD database, including 61,279 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.90 (61278 hom., cov: 29)
  • Exomes 𝑓: 1.0 (1 hom.)
• Consequence: DAG1 NM_004393.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.944
• Publications: 3 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: Genomics England PanelApp, Orphanet, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 3-49488611-A-T is Benign according to our data. Variant chr3-49488611-A-T is described in ClinVar as Benign. ClinVar VariationId is 1252410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.96 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+18178A>T		intron	N/A	NP_004384.5	Q14118
	DAG1	NM_001165928.4		c.-315-87A>T		intron	N/A	NP_001159400.3	Q14118
	DAG1	NM_001177634.3		c.-117+1196A>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+18178A>T		intron	N/A	ENSP00000312435.2	Q14118
	DAG1	ENST00000966350.1		c.-251A>T		5_prime_UTR	Exon 1 of 3	ENSP00000636409.1
	DAG1	ENST00000418588.6	TSL:3	c.-117+11711A>T		intron	N/A	ENSP00000405859.2	Q14118

Frequencies

GnomAD3 genomes AF: 0.903 AC: 135665 AN: 150262 Hom.: 61236 Cov.: 29

Gnomad AFR AF: 0.895

Gnomad AMI AF: 0.915

Gnomad AMR AF: 0.927

Gnomad ASJ AF: 0.861

Gnomad EAS AF: 0.983

Gnomad SAS AF: 0.969

Gnomad FIN AF: 0.865

Gnomad MID AF: 0.919

Gnomad NFE AF: 0.899

Gnomad OTH AF: 0.912

GnomAD4 exome AF: 1.00 AC: 2 AN: 2 Hom.: 1 Cov.: 0 AF XY: 1.00 AC XY: 2 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: 1.00 AC: 2 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.903 AC: 135753 AN: 150354 Hom.: 61278 Cov.: 29 AF XY: 0.902 AC XY: 66139 AN XY: 73294

African (AFR) AF: 0.895 AC: 36888 AN: 41194

American (AMR) AF: 0.927 AC: 13975 AN: 15082

Ashkenazi Jewish (ASJ) AF: 0.861 AC: 2953 AN: 3430

East Asian (EAS) AF: 0.982 AC: 5055 AN: 5146

South Asian (SAS) AF: 0.968 AC: 4635 AN: 4786

European-Finnish (FIN) AF: 0.865 AC: 8710 AN: 10066

Middle Eastern (MID) AF: 0.910 AC: 262 AN: 288

European-Non Finnish (NFE) AF: 0.899 AC: 60555 AN: 67386

Other (OTH) AF: 0.913 AC: 1887 AN: 2066

Alfa AF: 0.295 Hom.: 895

Bravo AF: 0.908

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.14
DANN	Benign	0.17
PhyloP100		-0.94
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs4855860; hg19: chr3-49526044;