rs2032474

Positions:

• chr22-33338410-T-C

Variant summary

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

The NM_133642.5(LARGE1):​c.1132-609A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.471 in 151,804 control chromosomes in the GnomAD database, including 18,498 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 0.47 (18498 hom., cov: 31)
• Consequence: LARGE1 NM_133642.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0290

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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LARGE1	NM_133642.5	c.1132-609A>G		intron_variant		ENST00000397394.8	NP_598397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LARGE1	ENST00000397394.8	c.1132-609A>G		intron_variant		5	NM_133642.5	ENSP00000380549	P1

Frequencies

GnomAD3 genomes AF: 0.471 AC: 71447 AN: 151686 Hom.: 18473 Cov.: 31

Gnomad AFR AF: 0.703

Gnomad AMI AF: 0.222

Gnomad AMR AF: 0.448

Gnomad ASJ AF: 0.439

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.486

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.370

Gnomad OTH AF: 0.456

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

GnomAD4 genome AF: 0.471 AC: 71522 AN: 151804 Hom.: 18498 Cov.: 31 AF XY: 0.468 AC XY: 34743 AN XY: 74172

Gnomad4 AFR AF: 0.703

Gnomad4 AMR AF: 0.448

Gnomad4 ASJ AF: 0.439

Gnomad4 EAS AF: 0.282

Gnomad4 SAS AF: 0.486

Gnomad4 FIN AF: 0.370

Gnomad4 NFE AF: 0.370

Gnomad4 OTH AF: 0.451

Alfa AF: 0.424 Hom.: 3426

Bravo AF: 0.487

Asia WGS AF: 0.355 AC: 1234 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	8.3
DANN	Benign	0.72

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: rs2032474; hg19: chr22-33734396;