chr3-49470079-T-G

Variant names:

• chr3-49470079-T-G
• rs4855840
• NM_001177643.3:c.-117+1024T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001177643.3(DAG1):​c.-117+1024T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.976 in 151,822 control chromosomes in the GnomAD database, including 72,418 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (72407 hom., cov: 32)
  • Exomes 𝑓: 1.0 (11 hom.)
• Consequence: DAG1 NM_001177643.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.340
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-49470079-T-G is Benign according to our data. Variant chr3-49470079-T-G is described in ClinVar as Benign. ClinVar VariationId is 1237933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001177643.3. 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_001177643.3		c.-117+1024T>G		intron	N/A	NP_001171114.2	Q14118
	DAG1	NM_004393.6	MANE Select	c.-471T>G		upstream_gene	N/A	NP_004384.5	Q14118
	DAG1	NM_001165928.4		c.-832T>G		upstream_gene	N/A	NP_001159400.3	Q14118

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DAG1	ENST00000469139.2	TSL:4	c.-117+1024T>G		intron	N/A	ENSP00000501165.2	Q14118
	DAG1	ENST00000882459.1		c.-384+1024T>G		intron	N/A	ENSP00000552518.1
	DAG1	ENST00000936846.1		c.-169+1024T>G		intron	N/A	ENSP00000606905.1

Frequencies

GnomAD3 genomes AF: 0.976 AC: 148043 AN: 151692 Hom.: 72357 Cov.: 32

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: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.987

GnomAD4 exome AF: 1.00 AC: 22 AN: 22 Hom.: 11 AF XY: 1.00 AC XY: 12 AN XY: 12

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: 20 AN: 20

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

GnomAD4 genome AF: 0.976 AC: 148147 AN: 151800 Hom.: 72407 Cov.: 32 AF XY: 0.976 AC XY: 72413 AN XY: 74180

African (AFR) AF: 0.916 AC: 37996 AN: 41486

American (AMR) AF: 0.992 AC: 15139 AN: 15256

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3470 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5146 AN: 5146

South Asian (SAS) AF: 1.00 AC: 4830 AN: 4832

European-Finnish (FIN) AF: 1.00 AC: 10408 AN: 10408

Middle Eastern (MID) AF: 1.00 AC: 292 AN: 292

European-Non Finnish (NFE) AF: 1.00 AC: 67875 AN: 67892

Other (OTH) AF: 0.987 AC: 2079 AN: 2106

Alfa AF: 0.986 Hom.: 9344

Bravo AF: 0.973

Asia WGS AF: 0.995 AC: 3459 AN: 3476

ClinVar

ClinVar submissions

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	-0.83
CADD	Benign	8.4
DANN	Benign	0.59
PhyloP100		0.34
PromoterAI		-0.0032	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4855840; hg19: chr3-49507512;