rs36002910

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_133642.5(LARGE1):c.576C>T(p.Pro192Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0295 in 1,614,018 control chromosomes in the GnomAD database, including 845 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 67 hom., cov: 32)

Exomes 𝑓: 0.030 ( 778 hom. )

Consequence

LARGE1
NM_133642.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.37

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 22-33604474-G-A is Benign according to our data. Variant chr22-33604474-G-A is described in ClinVar as [Benign]. Clinvar id is 95176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-33604474-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.37 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0232 (3531/152234) while in subpopulation NFE AF= 0.0326 (2216/68014). AF 95% confidence interval is 0.0315. There are 67 homozygotes in gnomad4. There are 1704 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 67 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LARGE1	NM_133642.5 linkuse as main transcript	c.576C>T	p.Pro192Pro	synonymous_variant	5/15	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.576C>T	p.Pro192Pro	synonymous_variant	5/15	5	NM_133642.5	ENSP00000380549.2		O95461-1

Frequencies

GnomAD3 genomes

AF:

0.0232

AC:

3532

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00579

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0241

Gnomad ASJ

AF:

0.0530

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0172

Gnomad FIN

AF:

0.0349

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0326

Gnomad OTH

AF:

0.0287

GnomAD3 exomes

AF:

0.0235

AC:

5905

AN:

251256

Hom.:

102

AF XY:

0.0240

AC XY:

3254

AN XY:

135778

show subpopulations

Gnomad AFR exome

AF:

0.00517

Gnomad AMR exome

AF:

0.0158

Gnomad ASJ exome

AF:

0.0499

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0151

Gnomad FIN exome

AF:

0.0318

Gnomad NFE exome

AF:

0.0304

Gnomad OTH exome

AF:

0.0277

GnomAD4 exome

AF:

0.0302

AC:

44099

AN:

1461784

Hom.:

778

Cov.:

AF XY:

0.0299

AC XY:

21733

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.00439

Gnomad4 AMR exome

AF:

0.0172

Gnomad4 ASJ exome

AF:

0.0491

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0162

Gnomad4 FIN exome

AF:

0.0328

Gnomad4 NFE exome

AF:

0.0332

Gnomad4 OTH exome

AF:

0.0276

GnomAD4 genome

AF:

0.0232

AC:

3531

AN:

152234

Hom.:

Cov.:

AF XY:

0.0229

AC XY:

1704

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00578

Gnomad4 AMR

AF:

0.0241

Gnomad4 ASJ

AF:

0.0530

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0172

Gnomad4 FIN

AF:

0.0349

Gnomad4 NFE

AF:

0.0326

Gnomad4 OTH

AF:

0.0284

Alfa

AF:

0.0279

Hom.:

Bravo

AF:

0.0217

Asia WGS

AF:

0.00895

AC:

AN:

3478

EpiCase

AF:

0.0334

EpiControl

AF:

0.0297

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2013	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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 15, 2012	- -

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	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. -

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

-0.58

CADD

Benign

3.1

DANN

Benign

0.67

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

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