22-33606745-A-G

Variant names:

• chr22-33606745-A-G
• rs695271
• NM_133642.5:c.492-2187T>C

Variant summary

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

The NM_133642.5(LARGE1):​c.492-2187T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.583 in 151,842 control chromosomes in the GnomAD database, including 27,545 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 0.58 (27545 hom., cov: 30)
• Consequence: LARGE1 NM_133642.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.49

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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.82 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LARGE1	NM_133642.5	c.492-2187T>C		intron_variant	Intron 4 of 14	ENST00000397394.8	NP_598397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LARGE1	ENST00000397394.8	c.492-2187T>C		intron_variant	Intron 4 of 14	5	NM_133642.5	ENSP00000380549.2

Frequencies

GnomAD3 genomes AF: 0.582 AC: 88368 AN: 151724 Hom.: 27491 Cov.: 30

Gnomad AFR AF: 0.827

Gnomad AMI AF: 0.510

Gnomad AMR AF: 0.486

Gnomad ASJ AF: 0.472

Gnomad EAS AF: 0.456

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.477

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.555

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

GnomAD4 genome AF: 0.583 AC: 88471 AN: 151842 Hom.: 27545 Cov.: 30 AF XY: 0.580 AC XY: 43024 AN XY: 74192

Gnomad4 AFR AF: 0.827

Gnomad4 AMR AF: 0.485

Gnomad4 ASJ AF: 0.472

Gnomad4 EAS AF: 0.457

Gnomad4 SAS AF: 0.471

Gnomad4 FIN AF: 0.477

Gnomad4 NFE AF: 0.497

Gnomad4 OTH AF: 0.550

Alfa AF: 0.465 Hom.: 3364

Bravo AF: 0.592

Asia WGS AF: 0.491 AC: 1706 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.47
DANN	Benign	0.42

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: rs695271; hg19: chr22-34002731;