chr22-33273506-G-C

Position:

• chr22-33273506-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_133642.5(LARGE1):​c.*921C>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 0.0665 in 398,660 control chromosomes in the GnomAD database, including 1,037 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (503 hom., cov: 32)
  • Exomes 𝑓: 0.061 (534 hom.)
• Consequence: LARGE1 NM_133642.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.103

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]

LARGE1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 22-33273506-G-C is Benign according to our data. Variant chr22-33273506-G-C is described in ClinVar as [Benign]. Clinvar id is 341414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LARGE1	NM_133642.5	c.*921C>G		3_prime_UTR_variant	15/15	ENST00000397394.8	NP_598397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LARGE1	ENST00000397394	c.*921C>G		3_prime_UTR_variant	15/15	5	NM_133642.5	ENSP00000380549.2

Frequencies

GnomAD3 genomes AF: 0.0754 AC: 11473 AN: 152128 Hom.: 494 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0678

Gnomad ASJ AF: 0.0873

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.0350

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0696

Gnomad OTH AF: 0.0770

GnomAD4 exome AF: 0.0608 AC: 14990 AN: 246414 Hom.: 534 Cov.: 0 AF XY: 0.0612 AC XY: 7646 AN XY: 124880

Gnomad4 AFR exome AF: 0.108

Gnomad4 AMR exome AF: 0.0526

Gnomad4 ASJ exome AF: 0.0800

Gnomad4 EAS exome AF: 0.0000437

Gnomad4 SAS exome AF: 0.0218

Gnomad4 FIN exome AF: 0.0468

Gnomad4 NFE exome AF: 0.0684

Gnomad4 OTH exome AF: 0.0693

GnomAD4 genome AF: 0.0756 AC: 11503 AN: 152246 Hom.: 503 Cov.: 32 AF XY: 0.0714 AC XY: 5314 AN XY: 74458

Gnomad4 AFR AF: 0.114

Gnomad4 AMR AF: 0.0675

Gnomad4 ASJ AF: 0.0873

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0176

Gnomad4 FIN AF: 0.0350

Gnomad4 NFE AF: 0.0696

Gnomad4 OTH AF: 0.0767

Alfa AF: 0.0752 Hom.: 82

Bravo AF: 0.0797

Asia WGS AF: 0.0220 AC: 76 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy type B6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 12, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.0
DANN	Benign	0.59

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: rs16992034; hg19: chr22-33669492;