rs62225294

Positions:

• chr22-33432111-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_133642.5(LARGE1):​c.892+50C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00633 in 1,421,380 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (34 hom.)
• Consequence: LARGE1 NM_133642.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.720

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 22-33432111-G-A is Benign according to our data. Variant chr22-33432111-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-33432111-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00473 (720/152258) while in subpopulation NFE AF= 0.00756 (514/68030). AF 95% confidence interval is 0.00702. There are 0 homozygotes in gnomad4. There are 341 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LARGE1	NM_133642.5	c.892+50C>T		intron_variant		ENST00000397394.8	NP_598397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LARGE1	ENST00000397394.8	c.892+50C>T		intron_variant		5	NM_133642.5	ENSP00000380549.2

Frequencies

GnomAD3 genomes AF: 0.00472 AC: 718 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00472

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00754

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00477 AC: 1187 AN: 248854 Hom.: 4 AF XY: 0.00487 AC XY: 655 AN XY: 134506

Gnomad AFR exome AF: 0.000807

Gnomad AMR exome AF: 0.00406

Gnomad ASJ exome AF: 0.00848

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00248

Gnomad FIN exome AF: 0.00294

Gnomad NFE exome AF: 0.00696

Gnomad OTH exome AF: 0.00478

GnomAD4 exome AF: 0.00653 AC: 8282 AN: 1269122 Hom.: 34 Cov.: 18 AF XY: 0.00645 AC XY: 4137 AN XY: 641104

Gnomad4 AFR exome AF: 0.00115

Gnomad4 AMR exome AF: 0.00382

Gnomad4 ASJ exome AF: 0.00891

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00231

Gnomad4 FIN exome AF: 0.00295

Gnomad4 NFE exome AF: 0.00756

Gnomad4 OTH exome AF: 0.00746

GnomAD4 genome AF: 0.00473 AC: 720 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.00458 AC XY: 341 AN XY: 74424

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00478

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00312

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.00756

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00639 Hom.: 0

Bravo AF: 0.00465

Asia WGS AF: 0.00144 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 15, 2012	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 26, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.36
DANN	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs62225294; hg19: chr22-33828097;