3-49510406-CTTT-CTTTTTTTTTTTTTTTT

Variant names:

• chr3-49510406-C-CTTTTTTTTTTTTT
• rs200455639
• NM_004393.6:c.-116-4_-116-3insTTTTTTTTTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_004393.6(DAG1):​c.-116-4_-116-3insTTTTTTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000129 in 773,950 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000013 (0 hom.)
• Consequence: DAG1 NM_004393.6 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.648
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

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.-116-4_-116-3insTTTTTTTTTTTTT		splice_region intron	N/A	NP_004384.5	Q14118
	DAG1	NM_001165928.4		c.-116-4_-116-3insTTTTTTTTTTTTT		splice_region intron	N/A	NP_001159400.3	Q14118
	DAG1	NM_001177634.3		c.-116-4_-116-3insTTTTTTTTTTTTT		splice_region 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.-116-4_-116-3insTTTTTTTTTTTTT		splice_region intron	N/A	ENSP00000312435.2	Q14118
	DAG1	ENST00000479935.1	TSL:1	n.192_193insTTTTTTTTTTTTT		non_coding_transcript_exon	Exon 1 of 2
	DAG1	ENST00000418588.6	TSL:3	c.-116-4_-116-3insTTTTTTTTTTTTT		splice_region intron	N/A	ENSP00000405859.2	Q14118

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000129 AC: 1 AN: 773950 Hom.: 0 Cov.: 11 AF XY: 0.00 AC XY: 0 AN XY: 409496

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 20098

American (AMR) AF: 0.00 AC: 0 AN: 39950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20858

East Asian (EAS) AF: 0.00 AC: 0 AN: 36324

South Asian (SAS) AF: 0.0000142 AC: 1 AN: 70338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2796

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 507784

Other (OTH) AF: 0.00 AC: 0 AN: 37774

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.65

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200455639; hg19: chr3-49547839;