rs86487

Positions:

• chr22-33626300-G-A
• chr22-33626300-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_133642.5(LARGE1):​c.435C>T​(p.Ala145=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.484 in 1,612,472 control chromosomes in the GnomAD database, including 194,473 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (14560 hom., cov: 32)
  • Exomes 𝑓: 0.49 (179913 hom.)
• Consequence: LARGE1 NM_133642.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.0540

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 22-33626300-G-A is Benign according to our data. Variant chr22-33626300-G-A is described in ClinVar as [Benign]. Clinvar id is 95175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-33626300-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.054 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.567 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LARGE1	NM_133642.5	c.435C>T	p.Ala145=	synonymous_variant	4/15	ENST00000397394.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LARGE1	ENST00000397394.8	c.435C>T	p.Ala145=	synonymous_variant	4/15	5	NM_133642.5	P1

Frequencies

GnomAD3 genomes AF: 0.408 AC: 62024 AN: 151924 Hom.: 14551 Cov.: 32

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.522

Gnomad AMR AF: 0.497

Gnomad ASJ AF: 0.537

Gnomad EAS AF: 0.584

Gnomad SAS AF: 0.518

Gnomad FIN AF: 0.524

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.490

Gnomad OTH AF: 0.436

GnomAD3 exomes AF: 0.488 AC: 122435 AN: 251030 Hom.: 30948 AF XY: 0.492 AC XY: 66673 AN XY: 135640

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.542

Gnomad ASJ exome AF: 0.542

Gnomad EAS exome AF: 0.572

Gnomad SAS exome AF: 0.507

Gnomad FIN exome AF: 0.525

Gnomad NFE exome AF: 0.488

Gnomad OTH exome AF: 0.501

GnomAD4 exome AF: 0.492 AC: 718511 AN: 1460430 Hom.: 179913 Cov.: 43 AF XY: 0.493 AC XY: 358346 AN XY: 726612

Gnomad4 AFR exome AF: 0.150

Gnomad4 AMR exome AF: 0.533

Gnomad4 ASJ exome AF: 0.542

Gnomad4 EAS exome AF: 0.595

Gnomad4 SAS exome AF: 0.511

Gnomad4 FIN exome AF: 0.522

Gnomad4 NFE exome AF: 0.493

Gnomad4 OTH exome AF: 0.488

GnomAD4 genome AF: 0.408 AC: 62037 AN: 152042 Hom.: 14560 Cov.: 32 AF XY: 0.411 AC XY: 30510 AN XY: 74312

Gnomad4 AFR AF: 0.161

Gnomad4 AMR AF: 0.497

Gnomad4 ASJ AF: 0.537

Gnomad4 EAS AF: 0.584

Gnomad4 SAS AF: 0.518

Gnomad4 FIN AF: 0.524

Gnomad4 NFE AF: 0.490

Gnomad4 OTH AF: 0.440

Alfa AF: 0.451 Hom.: 12597

Bravo AF: 0.398

Asia WGS AF: 0.518 AC: 1802 AN: 3478

EpiCase AF: 0.507

EpiControl AF: 0.506

ClinVar

Significance: Benign

Submissions summary: Benign:12

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	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 13, 2012	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -

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	Labcorp Genetics (formerly Invitae), Labcorp	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	-0.31
CADD	Benign	13
DANN	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs86487; hg19: chr22-34022284; COSMIC: COSV61657973;