rs137479

Positions:

• chr22-33239693-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
LARGE1	XM_024452302.2	c.1877+43509G>A		intron_variant			XP_024308070.1
LARGE1	XM_047441606.1	c.1274+43509G>A		intron_variant			XP_047297562.1
LARGE1	XR_002958722.2	n.2441+43509G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LARGE1	ENST00000608642.6	c.1730+64536G>A		intron_variant		5		ENSP00000476866
LARGE1	ENST00000609799.6	c.1452-72861G>A		intron_variant		5		ENSP00000476415
LARGE1	ENST00000610186.6	c.1877+43509G>A		intron_variant		5		ENSP00000476364

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

Gnomad4 AFR AF: 0.173

Gnomad4 AMR AF: 0.0995

Gnomad4 ASJ AF: 0.0458

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.0185

Gnomad4 FIN AF: 0.0338

Gnomad4 NFE AF: 0.0526

Gnomad4 OTH AF: 0.0672

Alfa AF: 0.0756 Hom.: 68

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs137479; hg19: chr22-33635679;