22-33273687-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_133642.5(LARGE1):c.*740A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 398,644 control chromosomes in the GnomAD database, including 144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.022 (108 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (36 hom.)
• Consequence: LARGE1 NM_133642.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.987

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 22-33273687-T-C is Benign according to our data. Variant chr22-33273687-T-C is described in ClinVar as [Benign]. Clinvar id is 341422.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.06 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LARGE1	NM_133642.5	c.*740A>G		3_prime_UTR_variant	15/15	ENST00000397394.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LARGE1	ENST00000397394.8	c.*740A>G		3_prime_UTR_variant	15/15	5	NM_133642.5	P1

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3391 AN: 152088 Hom.: 108 Cov.: 32

Gnomad AFR AF: 0.0621

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.0556

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.00243

Gnomad OTH AF: 0.0254

GnomAD4 exome AF: 0.00703 AC: 1732 AN: 246440 Hom.: 36 Cov.: 0 AF XY: 0.00701 AC XY: 876 AN XY: 124888

Gnomad4 AFR exome AF: 0.0645

Gnomad4 AMR exome AF: 0.0133

Gnomad4 ASJ exome AF: 0.0137

Gnomad4 EAS exome AF: 0.000874

Gnomad4 SAS exome AF: 0.0567

Gnomad4 FIN exome AF: 0.000481

Gnomad4 NFE exome AF: 0.00341

Gnomad4 OTH exome AF: 0.0158

GnomAD4 genome AF: 0.0223 AC: 3391 AN: 152204 Hom.: 108 Cov.: 32 AF XY: 0.0230 AC XY: 1715 AN XY: 74416

Gnomad4 AFR AF: 0.0620

Gnomad4 AMR AF: 0.0147

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00289

Gnomad4 SAS AF: 0.0556

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00243

Gnomad4 OTH AF: 0.0251

Alfa AF: 0.0161 Hom.: 10

Bravo AF: 0.0249

Asia WGS AF: 0.0320 AC: 112 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy type B6 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. -

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	-0.79
Cadd	Benign	6.8
Dann	Benign	0.69

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: rs116335813; hg19: chr22-33669673;