rs11913417

Positions:

• chr22-33283252-T-C

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.1827A>G​(p.Ser609=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00976 in 1,614,120 control chromosomes in the GnomAD database, including 386 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (90 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (296 hom.)
• Consequence: LARGE1 NM_133642.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.84

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=-0.92).
• BP6: Variant 22-33283252-T-C is Benign according to our data. Variant chr22-33283252-T-C is described in ClinVar as [Benign]. Clinvar id is 95169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-33283252-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.84 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LARGE1	NM_133642.5	c.1827A>G	p.Ser609=	synonymous_variant	13/15	ENST00000397394.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LARGE1	ENST00000397394.8	c.1827A>G	p.Ser609=	synonymous_variant	13/15	5	NM_133642.5	P1

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3393 AN: 152116 Hom.: 89 Cov.: 32

Gnomad AFR AF: 0.0581

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.0545

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.00370

Gnomad OTH AF: 0.0278

GnomAD3 exomes AF: 0.0159 AC: 3992 AN: 251418 Hom.: 100 AF XY: 0.0173 AC XY: 2352 AN XY: 135884

Gnomad AFR exome AF: 0.0603

Gnomad AMR exome AF: 0.00789

Gnomad ASJ exome AF: 0.0296

Gnomad EAS exome AF: 0.00283

Gnomad SAS exome AF: 0.0588

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.00441

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.00845 AC: 12357 AN: 1461886 Hom.: 296 Cov.: 32 AF XY: 0.00999 AC XY: 7263 AN XY: 727242

Gnomad4 AFR exome AF: 0.0637

Gnomad4 AMR exome AF: 0.00923

Gnomad4 ASJ exome AF: 0.0288

Gnomad4 EAS exome AF: 0.00159

Gnomad4 SAS exome AF: 0.0578

Gnomad4 FIN exome AF: 0.000599

Gnomad4 NFE exome AF: 0.00257

Gnomad4 OTH exome AF: 0.0149

GnomAD4 genome AF: 0.0223 AC: 3399 AN: 152234 Hom.: 90 Cov.: 32 AF XY: 0.0231 AC XY: 1719 AN XY: 74432

Gnomad4 AFR AF: 0.0581

Gnomad4 AMR AF: 0.0160

Gnomad4 ASJ AF: 0.0320

Gnomad4 EAS AF: 0.00290

Gnomad4 SAS AF: 0.0545

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00372

Gnomad4 OTH AF: 0.0275

Alfa AF: 0.0135 Hom.: 22

Bravo AF: 0.0252

Asia WGS AF: 0.0310 AC: 106 AN: 3478

EpiCase AF: 0.00583

EpiControl AF: 0.00634

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	Mar 31, 2014	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. -

Muscular dystrophy-dystroglycanopathy type B6 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
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. -

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	-0.92
CADD	Benign	0.15
DANN	Benign	0.36

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: rs11913417; hg19: chr22-33679238;