Variant chr22-33277024-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.2073+36C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,600,152 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0089 ( 9 hom., cov: 33)

Exomes 𝑓: 0.011 ( 112 hom. )

Consequence

LARGE1
NM_133642.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.507

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=-0.83).

BP6

Variant 22-33277024-G-A is Benign according to our data. Variant chr22-33277024-G-A is described in ClinVar as [Benign]. Clinvar id is 158806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-33277024-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0089 (1355/152194) while in subpopulation NFE AF= 0.0128 (870/67998). AF 95% confidence interval is 0.0121. There are 9 homozygotes in gnomad4. There are 664 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LARGE1	NM_133642.5 linkuse as main transcript	c.2073+36C>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.2073+36C>T		intron_variant		5	NM_133642.5	P1	O95461-1

Frequencies

GnomAD3 genomes

AF:

0.00889

AC:

1352

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00253

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0113

Gnomad ASJ

AF:

0.0303

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00808

Gnomad FIN

AF:

0.00161

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0128

Gnomad OTH

AF:

0.0129

GnomAD3 exomes

AF:

0.00904

AC:

2266

AN:

250560

Hom.:

AF XY:

0.00928

AC XY:

1257

AN XY:

135506

show subpopulations

Gnomad AFR exome

AF:

0.00203

Gnomad AMR exome

AF:

0.00668

Gnomad ASJ exome

AF:

0.0302

Gnomad EAS exome

AF:

0.000435

Gnomad SAS exome

AF:

0.00647

Gnomad FIN exome

AF:

0.00148

Gnomad NFE exome

AF:

0.0121

Gnomad OTH exome

AF:

0.0147

GnomAD4 exome

AF:

0.0110

AC:

15862

AN:

1447958

Hom.:

112

Cov.:

AF XY:

0.0109

AC XY:

7856

AN XY:

721128

show subpopulations

Gnomad4 AFR exome

AF:

0.00202

Gnomad4 AMR exome

AF:

0.00709

Gnomad4 ASJ exome

AF:

0.0294

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.00750

Gnomad4 FIN exome

AF:

0.00174

Gnomad4 NFE exome

AF:

0.0120

Gnomad4 OTH exome

AF:

0.0111

GnomAD4 genome

AF:

0.00890

AC:

1355

AN:

152194

Hom.:

Cov.:

AF XY:

0.00892

AC XY:

664

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.00253

Gnomad4 AMR

AF:

0.0113

Gnomad4 ASJ

AF:

0.0303

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00830

Gnomad4 FIN

AF:

0.00161

Gnomad4 NFE

AF:

0.0128

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.0131

Hom.:

Bravo

AF:

0.00953

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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

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

-0.83

CADD

Benign

0.43

DANN

Benign

0.51

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