rs5999086

Positions:

• chr22-33750381-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_133642.5(LARGE1):​c.106+10990T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 152,090 control chromosomes in the GnomAD database, including 6,494 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 0.24 (6494 hom., cov: 33)
• Consequence: LARGE1 NM_133642.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.109

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]

LARGE-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LARGE1	NM_133642.5	c.106+10990T>C		intron_variant		ENST00000397394.8	NP_598397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LARGE1	ENST00000397394.8	c.106+10990T>C		intron_variant		5	NM_133642.5	ENSP00000380549.2

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36668 AN: 151972 Hom.: 6469 Cov.: 33

Gnomad AFR AF: 0.510

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.0868

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.0626

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.213

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

GnomAD4 genome AF: 0.242 AC: 36730 AN: 152090 Hom.: 6494 Cov.: 33 AF XY: 0.236 AC XY: 17566 AN XY: 74364

Gnomad4 AFR AF: 0.510

Gnomad4 AMR AF: 0.141

Gnomad4 ASJ AF: 0.0868

Gnomad4 EAS AF: 0.204

Gnomad4 SAS AF: 0.0622

Gnomad4 FIN AF: 0.135

Gnomad4 NFE AF: 0.143

Gnomad4 OTH AF: 0.213

Alfa AF: 0.140 Hom.: 2551

Bravo AF: 0.253

Asia WGS AF: 0.151 AC: 526 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.1
DANN	Benign	0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs5999086; hg19: chr22-34146368;