chr22-33239693-C-T

Variant names:

• chr22-33239693-C-T
• rs137479
• ENST00000610186.6:c.1877+43509G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000610186.6(LARGE1):​c.1877+43509G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0858 in 151,680 control chromosomes in the GnomAD database, including 807 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.086 (807 hom., cov: 27)
• Consequence: LARGE1 ENST00000610186.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.117
• Publications: 0 publications found

Genes affected

LARGE1 (HGNC:6511): (LARGE xylosyl- and glucuronyltransferase 1) This gene encodes a member of the N-acetylglucosaminyltransferase gene family. It encodes a glycosyltransferase which participates in glycosylation of alpha-dystroglycan, and may carry out the synthesis of glycoprotein and glycosphingolipid sugar chains. It may also be involved in the addition of a repeated disaccharide unit. The protein encoded by this gene is the glycotransferase that adds the final xylose and glucuronic acid to alpha-dystroglycan and thereby allows alpha-dystroglycan to bind ligands including laminin 211 and neurexin. Mutations in this gene cause several forms of congenital muscular dystrophy characterized by cognitive disability and abnormal glycosylation of alpha-dystroglycan. Alternative splicing of this gene results in multiple transcript variants that encode the same protein. [provided by RefSeq, May 2018]

LARGE1 Gene-Disease associations (from GenCC):

• muscular dystrophy-dystroglycanopathy type B6

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• congenital muscular dystrophy with intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LARGE1	XM_024452302.2	c.1877+43509G>A		intron_variant	Intron 14 of 14		XP_024308070.1
LARGE1	XM_047441606.1	c.1274+43509G>A		intron_variant	Intron 9 of 9		XP_047297562.1
LARGE1	XR_002958722.2	n.2441+43509G>A		intron_variant	Intron 13 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LARGE1	ENST00000610186.6	c.1877+43509G>A		intron_variant	Intron 12 of 12	5		ENSP00000476364.2
LARGE1	ENST00000608642.6	c.1730+64536G>A		intron_variant	Intron 11 of 11	5		ENSP00000476866.2
LARGE1	ENST00000609799.6	c.1452-72861G>A		intron_variant	Intron 10 of 10	5		ENSP00000476415.2

Frequencies

GnomAD3 genomes AF: 0.0857 AC: 12986 AN: 151562 Hom.: 805 Cov.: 27

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0990

Gnomad ASJ AF: 0.0458

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0191

Gnomad FIN AF: 0.0338

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0526

Gnomad OTH AF: 0.0650

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0858 AC: 13018 AN: 151680 Hom.: 807 Cov.: 27 AF XY: 0.0825 AC XY: 6113 AN XY: 74104

African (AFR) AF: 0.173 AC: 7154 AN: 41302

American (AMR) AF: 0.0995 AC: 1518 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.0458 AC: 159 AN: 3468

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5152

South Asian (SAS) AF: 0.0185 AC: 89 AN: 4804

European-Finnish (FIN) AF: 0.0338 AC: 356 AN: 10528

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0526 AC: 3569 AN: 67872

Other (OTH) AF: 0.0672 AC: 141 AN: 2098

Alfa AF: 0.0794 Hom.: 79

Bravo AF: 0.0940

Asia WGS AF: 0.0340 AC: 120 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	3.8
DANN	Benign	0.63
PhyloP100		0.12

Splicing

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

Other links and lift over

dbSNP: rs137479; hg19: chr22-33635679;