Variant 22-33432111-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_133642.5(LARGE1):c.892+50C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00633 in 1,421,380 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0065 ( 34 hom. )

Consequence

LARGE1
NM_133642.5 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.720

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 22-33432111-G-A is Benign according to our data. Variant chr22-33432111-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-33432111-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00473 (720/152258) while in subpopulation NFE AF= 0.00756 (514/68030). AF 95% confidence interval is 0.00702. There are 0 homozygotes in gnomad4. There are 341 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LARGE1	NM_133642.5 linkuse as main transcript	c.892+50C>T		intron_variant		ENST00000397394.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LARGE1	ENST00000397394.8 linkuse as main transcript	c.892+50C>T		intron_variant		5	NM_133642.5	P1	O95461-1

Frequencies

GnomAD3 genomes

AF:

0.00472

AC:

718

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00472

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00754

Gnomad OTH

AF:

0.00622

GnomAD3 exomes

AF:

0.00477

AC:

1187

AN:

248854

Hom.:

AF XY:

0.00487

AC XY:

655

AN XY:

134506

show subpopulations

Gnomad AFR exome

AF:

0.000807

Gnomad AMR exome

AF:

0.00406

Gnomad ASJ exome

AF:

0.00848

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00248

Gnomad FIN exome

AF:

0.00294

Gnomad NFE exome

AF:

0.00696

Gnomad OTH exome

AF:

0.00478

GnomAD4 exome

AF:

0.00653

AC:

8282

AN:

1269122

Hom.:

Cov.:

AF XY:

0.00645

AC XY:

4137

AN XY:

641104

show subpopulations

Gnomad4 AFR exome

AF:

0.00115

Gnomad4 AMR exome

AF:

0.00382

Gnomad4 ASJ exome

AF:

0.00891

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00231

Gnomad4 FIN exome

AF:

0.00295

Gnomad4 NFE exome

AF:

0.00756

Gnomad4 OTH exome

AF:

0.00746

GnomAD4 genome

AF:

0.00473

AC:

720

AN:

152258

Hom.:

Cov.:

AF XY:

0.00458

AC XY:

341

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00128

Gnomad4 AMR

AF:

0.00478

Gnomad4 ASJ

AF:

0.00692

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00312

Gnomad4 FIN

AF:

0.00226

Gnomad4 NFE

AF:

0.00756

Gnomad4 OTH

AF:

0.00616

Alfa

AF:

0.00639

Hom.:

Bravo

AF:

0.00465

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 15, 2012	- -
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	-	- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 26, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.36

DANN

Benign

0.57

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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