rs115076367

chr22-33382042-A-Gchr22-33382042-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_133642.5(LARGE1):c.1008T>C(p.Asp336=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,614,104 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (33 hom.)
• Consequence: LARGE1 NM_133642.5 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.784

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=-0.48).
• BP6: Variant 22-33382042-A-G is Benign according to our data. Variant chr22-33382042-A-G is described in ClinVar as [Benign]. Clinvar id is 158804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-33382042-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.784 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00198 (302/152286) while in subpopulation EAS AF= 0.0459 (237/5164). AF 95% confidence interval is 0.0411. There are 7 homozygotes in gnomad4. There are 169 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LARGE1	NM_133642.5	c.1008T>C	p.Asp336=	splice_region_variant, synonymous_variant	9/15	ENST00000397394.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LARGE1	ENST00000397394.8	c.1008T>C	p.Asp336=	splice_region_variant, synonymous_variant	9/15	5	NM_133642.5	P1

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 304 AN: 152168 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0462

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00377 AC: 947 AN: 251326 Hom.: 17 AF XY: 0.00331 AC XY: 450 AN XY: 135840

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0488

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00123 AC: 1799 AN: 1461818 Hom.: 33 Cov.: 31 AF XY: 0.00121 AC XY: 877 AN XY: 727216

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0362

Gnomad4 SAS exome AF: 0.000881

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.0000342

Gnomad4 OTH exome AF: 0.00373

GnomAD4 genome AF: 0.00198 AC: 302 AN: 152286 Hom.: 7 Cov.: 32 AF XY: 0.00227 AC XY: 169 AN XY: 74468

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0459

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00240 Hom.: 7

Bravo AF: 0.00188

Asia WGS AF: 0.0230 AC: 81 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2016	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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 04, 2013	- -

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	Jan 31, 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	-0.48
Cadd	Benign	9.0
Dann	Benign	0.88

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: rs115076367; hg19: chr22-33778028;