22-33170601-C-T

Position:

• chr22-33170601-C-T

Variant summary

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

The ENST00000610186.6(LARGE1):​c.1878-3769G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 151,916 control chromosomes in the GnomAD database, including 13,918 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 0.42 (13918 hom., cov: 31)
• 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]

LARGE1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.444 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LARGE1	XM_024452302.2	c.1878-3769G>A		intron_variant			XP_024308070.1
LARGE1	XM_047441606.1	c.1275-3769G>A		intron_variant			XP_047297562.1
LARGE1	XR_002958722.2	n.2442-3769G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LARGE1	ENST00000610186.6	c.1878-3769G>A		intron_variant		5		ENSP00000476364.2
LARGE1	ENST00000608642.6	c.1731-3769G>A		intron_variant		5		ENSP00000476866.2
LARGE1	ENST00000609799.6	c.1452-3769G>A		intron_variant		5		ENSP00000476415.2

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64197 AN: 151798 Hom.: 13905 Cov.: 31

Gnomad AFR AF: 0.434

Gnomad AMI AF: 0.654

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.422

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.449

Gnomad OTH AF: 0.426

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

GnomAD4 genome AF: 0.423 AC: 64250 AN: 151916 Hom.: 13918 Cov.: 31 AF XY: 0.417 AC XY: 30959 AN XY: 74250

Gnomad4 AFR AF: 0.434

Gnomad4 AMR AF: 0.393

Gnomad4 ASJ AF: 0.418

Gnomad4 EAS AF: 0.153

Gnomad4 SAS AF: 0.311

Gnomad4 FIN AF: 0.422

Gnomad4 NFE AF: 0.449

Gnomad4 OTH AF: 0.422

Alfa AF: 0.437 Hom.: 12784

Bravo AF: 0.429

Asia WGS AF: 0.245 AC: 852 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.8
DANN	Benign	0.46

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4821132; hg19: chr22-33566587;