22-33274220-C-T

Position:

chr22-33274220-C-T

Variant summary

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

The NM_133642.5(LARGE1):c.*207G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0303 in 632,362 control chromosomes in the GnomAD database, including 384 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 104 hom., cov: 32)

Exomes 𝑓: 0.029 ( 280 hom. )

Consequence

LARGE1
NM_133642.5 3_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.913

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 22-33274220-C-T is Benign according to our data. Variant chr22-33274220-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 341428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-33274220-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0329 (5004/152278) while in subpopulation AFR AF= 0.0483 (2008/41560). AF 95% confidence interval is 0.0466. There are 104 homozygotes in gnomad4. There are 2402 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 104 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LARGE1	NM_133642.5 linkuse as main transcript	c.*207G>A		3_prime_UTR_variant	15/15	ENST00000397394.8	NP_598397.1	O95461-1X5DR28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LARGE1	ENST00000397394 linkuse as main transcript	c.*207G>A		3_prime_UTR_variant	15/15	5	NM_133642.5	ENSP00000380549.2		O95461-1

Frequencies

GnomAD3 genomes

AF:

0.0328

AC:

4998

AN:

152160

Hom.:

104

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0220

Gnomad ASJ

AF:

0.0196

Gnomad EAS

AF:

0.0286

Gnomad SAS

AF:

0.0303

Gnomad FIN

AF:

0.0300

Gnomad MID

AF:

0.0255

Gnomad NFE

AF:

0.0280

Gnomad OTH

AF:

0.0325

GnomAD4 exome

AF:

0.0295

AC:

14155

AN:

480084

Hom.:

280

Cov.:

AF XY:

0.0293

AC XY:

7493

AN XY:

255756

show subpopulations

Gnomad4 AFR exome

AF:

0.0508

Gnomad4 AMR exome

AF:

0.0181

Gnomad4 ASJ exome

AF:

0.0225

Gnomad4 EAS exome

AF:

0.0389

Gnomad4 SAS exome

AF:

0.0329

Gnomad4 FIN exome

AF:

0.0288

Gnomad4 NFE exome

AF:

0.0283

Gnomad4 OTH exome

AF:

0.0280

GnomAD4 genome

AF:

0.0329

AC:

5004

AN:

152278

Hom.:

104

Cov.:

AF XY:

0.0323

AC XY:

2402

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0483

Gnomad4 AMR

AF:

0.0219

Gnomad4 ASJ

AF:

0.0196

Gnomad4 EAS

AF:

0.0284

Gnomad4 SAS

AF:

0.0307

Gnomad4 FIN

AF:

0.0300

Gnomad4 NFE

AF:

0.0280

Gnomad4 OTH

AF:

0.0317

Alfa

AF:

0.0305

Hom.:

Bravo

AF:

0.0331

Asia WGS

AF:

0.0260

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 provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

7.8

DANN

Benign

0.40

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