chr3-49510793-A-G

Variant names:

• chr3-49510793-A-G
• rs116717961
• NM_004393.6:c.259A>G

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.259A>G​(p.Ile87Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,614,076 control chromosomes in the GnomAD database, including 113 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. I87I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0079 (7 hom., cov: 31)
  • Exomes 𝑓: 0.011 (106 hom.)
• Consequence: DAG1 NM_004393.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 2.26
• 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: G2P, Genomics England PanelApp, Orphanet
• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• 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=0.012165487).
• BP6: Variant 3-49510793-A-G is Benign according to our data. Variant chr3-49510793-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00791 (1204/152204) while in subpopulation AMR AF = 0.0193 (295/15280). AF 95% confidence interval is 0.0175. There are 7 homozygotes in GnomAd4. There are 526 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.259A>G	p.Ile87Val	missense	Exon 2 of 3	NP_004384.5
	DAG1	NM_001165928.4		c.259A>G	p.Ile87Val	missense	Exon 5 of 6	NP_001159400.3
	DAG1	NM_001177634.3		c.259A>G	p.Ile87Val	missense	Exon 5 of 6	NP_001171105.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DAG1	ENST00000308775.7	TSL:1 MANE Select	c.259A>G	p.Ile87Val	missense	Exon 2 of 3	ENSP00000312435.2
	DAG1	ENST00000479935.1	TSL:1	n.570A>G		non_coding_transcript_exon	Exon 1 of 2
	DAG1	ENST00000418588.6	TSL:3	c.259A>G	p.Ile87Val	missense	Exon 3 of 4	ENSP00000405859.2

Frequencies

GnomAD3 genomes AF: 0.00791 AC: 1203 AN: 152086 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0193

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00453

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00809 AC: 2032 AN: 251050 AF XY: 0.00761

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.0159

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00610

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.0107 AC: 15642 AN: 1461872 Hom.: 106 Cov.: 74 AF XY: 0.0102 AC XY: 7433 AN XY: 727238

African (AFR) AF: 0.00137 AC: 46 AN: 33480

American (AMR) AF: 0.0164 AC: 734 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00398 AC: 104 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86252

European-Finnish (FIN) AF: 0.00640 AC: 342 AN: 53418

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0124 AC: 13836 AN: 1112004

Other (OTH) AF: 0.00942 AC: 569 AN: 60396

GnomAD4 genome AF: 0.00791 AC: 1204 AN: 152204 Hom.: 7 Cov.: 31 AF XY: 0.00707 AC XY: 526 AN XY: 74424

African (AFR) AF: 0.00217 AC: 90 AN: 41526

American (AMR) AF: 0.0193 AC: 295 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00453 AC: 48 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0107 AC: 731 AN: 68012

Other (OTH) AF: 0.0123 AC: 26 AN: 2116

Alfa AF: 0.00972 Hom.: 51

Bravo AF: 0.00922

TwinsUK AF: 0.0127 AC: 47

ALSPAC AF: 0.00986 AC: 38

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0116 AC: 100

ExAC AF: 0.00719 AC: 873

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0111

EpiControl AF: 0.0113

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	2	not specified (2)
-	-	1	DAG1-related disorder (1)
-	-	1	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9;C4511963:Autosomal recessive limb-girdle muscular dystrophy type 2P (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	15
DANN	Benign	0.87
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.096	D
MutationAssessor	Benign	1.6	L
PhyloP100		2.3
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.23
Sift	Benign	0.25	T
Sift4G	Benign	0.54	T
Polyphen		0.0060	B
Vest4		0.17
MVP		0.72
MPC		0.23
ClinPred		0.0052	T
GERP RS		4.3
Varity_R		0.043
gMVP		0.35
Mutation Taster		=99/1	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: rs116717961; hg19: chr3-49548226;