rs117209107

Variant names:

• chr3-49530842-G-A
• rs117209107
• NM_004393.6:c.331G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004393.6(DAG1):​c.331G>A​(p.Asp111Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000802 in 1,614,210 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D111D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00096 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (3 hom.)
• Consequence: DAG1 NM_004393.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:9
• Conservation: PhyloP100: 4.22
• Publications: 12 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 (MetaRNN=0.007886469).
• BP6: Variant 3-49530842-G-A is Benign according to our data. Variant chr3-49530842-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 208541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000958 (146/152326) while in subpopulation EAS AF = 0.0252 (131/5194). AF 95% confidence interval is 0.0217. There are 4 homozygotes in GnomAd4. There are 94 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

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.331G>A	p.Asp111Asn	missense	Exon 3 of 3	NP_004384.5	Q14118
	DAG1	NM_001165928.4		c.331G>A	p.Asp111Asn	missense	Exon 6 of 6	NP_001159400.3	Q14118
	DAG1	NM_001177634.3		c.331G>A	p.Asp111Asn	missense	Exon 6 of 6	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.331G>A	p.Asp111Asn	missense	Exon 3 of 3	ENSP00000312435.2	Q14118
	DAG1	ENST00000479935.1	TSL:1	n.642G>A		non_coding_transcript_exon	Exon 2 of 2
	DAG1	ENST00000418588.6	TSL:3	c.331G>A	p.Asp111Asn	missense	Exon 4 of 4	ENSP00000405859.2	Q14118

Frequencies

GnomAD3 genomes AF: 0.000972 AC: 148 AN: 152208 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0252

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00216 AC: 543 AN: 251166 AF XY: 0.00199

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.0268

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000786 AC: 1149 AN: 1461884 Hom.: 3 Cov.: 32 AF XY: 0.000813 AC XY: 591 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000157 AC: 7 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000727 AC: 19 AN: 26136

East Asian (EAS) AF: 0.0238 AC: 945 AN: 39700

South Asian (SAS) AF: 0.00104 AC: 90 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1112006

Other (OTH) AF: 0.000778 AC: 47 AN: 60396

GnomAD4 genome AF: 0.000958 AC: 146 AN: 152326 Hom.: 4 Cov.: 32 AF XY: 0.00126 AC XY: 94 AN XY: 74480

African (AFR) AF: 0.00 AC: 0 AN: 41568

American (AMR) AF: 0.000131 AC: 2 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.0252 AC: 131 AN: 5194

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000991 Hom.: 3

Bravo AF: 0.00134

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00199 AC: 242

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
1	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2P (2)
-	-	2	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9;C4511963:Autosomal recessive limb-girdle muscular dystrophy type 2P (2)
-	-	2	not specified (2)
-	-	1	DAG1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.029
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0079	T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	0.64	N
PhyloP100		4.2
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.78
Sift	Benign	0.28	T
Sift4G	Benign	0.53	T
Polyphen		0.16	B
Vest4		0.68
MVP		0.76
MPC		0.27
ClinPred		0.025	T
GERP RS		5.9
Varity_R		0.19
gMVP		0.64
Mutation Taster		=54/46	polymorphism

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: rs117209107; hg19: chr3-49568275;