chr3-49470414-G-A

Variant names:

• chr3-49470414-G-A
• rs4855839
• NM_004393.6:c.-136G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_004393.6(DAG1):​c.-136G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 152,058 control chromosomes in the GnomAD database, including 15,821 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15805 hom., cov: 33)
  • Exomes 𝑓: 0.51 (16 hom.)
• Consequence: DAG1 NM_004393.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0430
• Publications: 16 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 3-49470414-G-A is Benign according to our data. Variant chr3-49470414-G-A is described in ClinVar as Benign. ClinVar VariationId is 380775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.908 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.-136G>A		5_prime_UTR	Exon 1 of 3	NP_004384.5	Q14118
	DAG1	NM_001165928.4		c.-497G>A		5_prime_UTR	Exon 1 of 6	NP_001159400.3	Q14118
	DAG1	NM_001177634.3		c.-440G>A		5_prime_UTR	Exon 1 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.-136G>A		5_prime_UTR	Exon 1 of 3	ENSP00000312435.2	Q14118
	DAG1	ENST00000418588.6	TSL:3	c.-188G>A		5_prime_UTR	Exon 1 of 4	ENSP00000405859.2	Q14118
	DAG1	ENST00000428779.7	TSL:3	c.-440G>A		5_prime_UTR	Exon 1 of 6	ENSP00000401382.3	Q14118

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66326 AN: 151810 Hom.: 15796 Cov.: 33

Gnomad AFR AF: 0.342

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.578

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.930

Gnomad SAS AF: 0.687

Gnomad FIN AF: 0.346

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.435

GnomAD4 exome AF: 0.507 AC: 70 AN: 138 Hom.: 16 Cov.: 0 AF XY: 0.517 AC XY: 60 AN XY: 116

African (AFR) AF: 0.333 AC: 2 AN: 6

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AF: 0.500 AC: 1 AN: 2

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 1.00 AC: 2 AN: 2

European-Non Finnish (NFE) AF: 0.525 AC: 64 AN: 122

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.437 AC: 66364 AN: 151920 Hom.: 15805 Cov.: 33 AF XY: 0.443 AC XY: 32871 AN XY: 74266

African (AFR) AF: 0.341 AC: 14156 AN: 41470

American (AMR) AF: 0.579 AC: 8831 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 1206 AN: 3468

East Asian (EAS) AF: 0.930 AC: 4804 AN: 5164

South Asian (SAS) AF: 0.686 AC: 3312 AN: 4830

European-Finnish (FIN) AF: 0.346 AC: 3650 AN: 10546

Middle Eastern (MID) AF: 0.387 AC: 113 AN: 292

European-Non Finnish (NFE) AF: 0.426 AC: 28878 AN: 67866

Other (OTH) AF: 0.440 AC: 929 AN: 2110

Alfa AF: 0.434 Hom.: 11763

Bravo AF: 0.451

Asia WGS AF: 0.775 AC: 2669 AN: 3452

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	15
DANN	Benign	0.89
PhyloP100		0.043
PromoterAI		0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs4855839; hg19: chr3-49507847;