rs17722172

Positions:

• chr22-33274598-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_133642.5(LARGE1):​c.2100C>T​(p.Asn700=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0598 in 1,613,914 control chromosomes in the GnomAD database, including 3,243 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (220 hom., cov: 32)
  • Exomes 𝑓: 0.061 (3023 hom.)
• Consequence: LARGE1 NM_133642.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.165

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 22-33274598-G-A is Benign according to our data. Variant chr22-33274598-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-33274598-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.165 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0677 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LARGE1	NM_133642.5	c.2100C>T	p.Asn700=	synonymous_variant	15/15	ENST00000397394.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LARGE1	ENST00000397394.8	c.2100C>T	p.Asn700=	synonymous_variant	15/15	5	NM_133642.5	P1

Frequencies

GnomAD3 genomes AF: 0.0463 AC: 7044 AN: 152122 Hom.: 220 Cov.: 32

Gnomad AFR AF: 0.0127

Gnomad AMI AF: 0.0706

Gnomad AMR AF: 0.0557

Gnomad ASJ AF: 0.0867

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.0350

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0694

Gnomad OTH AF: 0.0564

GnomAD3 exomes AF: 0.0472 AC: 11842 AN: 250860 Hom.: 379 AF XY: 0.0477 AC XY: 6468 AN XY: 135660

Gnomad AFR exome AF: 0.0106

Gnomad AMR exome AF: 0.0335

Gnomad ASJ exome AF: 0.0807

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0194

Gnomad FIN exome AF: 0.0390

Gnomad NFE exome AF: 0.0696

Gnomad OTH exome AF: 0.0626

GnomAD4 exome AF: 0.0612 AC: 89503 AN: 1461674 Hom.: 3023 Cov.: 31 AF XY: 0.0603 AC XY: 43876 AN XY: 727178

Gnomad4 AFR exome AF: 0.0111

Gnomad4 AMR exome AF: 0.0352

Gnomad4 ASJ exome AF: 0.0798

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0198

Gnomad4 FIN exome AF: 0.0443

Gnomad4 NFE exome AF: 0.0695

Gnomad4 OTH exome AF: 0.0613

GnomAD4 genome AF: 0.0463 AC: 7042 AN: 152240 Hom.: 220 Cov.: 32 AF XY: 0.0436 AC XY: 3245 AN XY: 74426

Gnomad4 AFR AF: 0.0127

Gnomad4 AMR AF: 0.0555

Gnomad4 ASJ AF: 0.0867

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0143

Gnomad4 FIN AF: 0.0350

Gnomad4 NFE AF: 0.0693

Gnomad4 OTH AF: 0.0563

Alfa AF: 0.0633 Hom.: 538

Bravo AF: 0.0456

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.0702

EpiControl AF: 0.0711

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 25, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 05, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Muscular dystrophy-dystroglycanopathy type B6 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	2.8
DANN	Benign	0.89

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: rs17722172; hg19: chr22-33670584;