chr22-33283291-C-T

Position:

chr22-33283291-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_133642.5(LARGE1):c.1788G>A(p.Ala596Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00339 in 1,614,108 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0022 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 16 hom. )

Consequence

LARGE1
NM_133642.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7

Conservation

PhyloP100: -5.16

Variant links:

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 links:

LARGE1 (HGNC:):

LARGE1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 22-33283291-C-T is Benign according to our data. Variant chr22-33283291-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167250.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2, Benign=3}. Variant chr22-33283291-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-5.16 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00218 (332/152222) while in subpopulation NFE AF= 0.00322 (219/68010). AF 95% confidence interval is 0.00287. There are 2 homozygotes in gnomad4. There are 145 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LARGE1	NM_133642.5 linkuse as main transcript	c.1788G>A	p.Ala596Ala	synonymous_variant	13/15	ENST00000397394.8	NP_598397.1	O95461-1X5DR28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LARGE1	ENST00000397394.8 linkuse as main transcript	c.1788G>A	p.Ala596Ala	synonymous_variant	13/15	5	NM_133642.5	ENSP00000380549.2		O95461-1

Frequencies

GnomAD3 genomes

AF:

0.00218

AC:

332

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.0147

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00146

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00322

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00265

AC:

667

AN:

251390

Hom.:

AF XY:

0.00272

AC XY:

370

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.0135

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00163

Gnomad FIN exome

AF:

0.00305

Gnomad NFE exome

AF:

0.00329

Gnomad OTH exome

AF:

0.00342

GnomAD4 exome

AF:

0.00352

AC:

5147

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00347

AC XY:

2526

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.0140

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00189

Gnomad4 FIN exome

AF:

0.00270

Gnomad4 NFE exome

AF:

0.00382

Gnomad4 OTH exome

AF:

0.00308

GnomAD4 genome

AF:

0.00218

AC:

332

AN:

152222

Hom.:

Cov.:

AF XY:

0.00195

AC XY:

145

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.000602

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.0147

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00146

Gnomad4 FIN

AF:

0.00207

Gnomad4 NFE

AF:

0.00322

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00338

Hom.:

Bravo

AF:

0.00203

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00316

EpiControl

AF:

0.00314

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	LARGE1: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 16, 2017	- -

Muscular dystrophy-dystroglycanopathy type B6

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 24, 2014	- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

LARGE1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.046

DANN

Benign

0.42

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over