22-33350540-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_133642.5(LARGE1):​c.1132-12739C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 152,128 control chromosomes in the GnomAD database, including 4,100 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.21 ( 4100 hom., cov: 32)

Consequence

LARGE1
NM_133642.5 intron

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.518
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LARGE1NM_133642.5 linkuse as main transcriptc.1132-12739C>G intron_variant ENST00000397394.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LARGE1ENST00000397394.8 linkuse as main transcriptc.1132-12739C>G intron_variant 5 NM_133642.5 P1O95461-1

Frequencies

GnomAD3 genomes
AF:
0.208
AC:
31598
AN:
152010
Hom.:
4096
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0534
Gnomad AMI
AF:
0.322
Gnomad AMR
AF:
0.301
Gnomad ASJ
AF:
0.358
Gnomad EAS
AF:
0.454
Gnomad SAS
AF:
0.229
Gnomad FIN
AF:
0.229
Gnomad MID
AF:
0.253
Gnomad NFE
AF:
0.247
Gnomad OTH
AF:
0.248
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
AF:
0.208
AC:
31609
AN:
152128
Hom.:
4100
Cov.:
32
AF XY:
0.210
AC XY:
15611
AN XY:
74386
show subpopulations
Gnomad4 AFR
AF:
0.0532
Gnomad4 AMR
AF:
0.301
Gnomad4 ASJ
AF:
0.358
Gnomad4 EAS
AF:
0.454
Gnomad4 SAS
AF:
0.228
Gnomad4 FIN
AF:
0.229
Gnomad4 NFE
AF:
0.247
Gnomad4 OTH
AF:
0.248
Alfa
AF:
0.0962
Hom.:
144
Bravo
AF:
0.213

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.90
CADD
Benign
5.8
DANN
Benign
0.63

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs2267193; hg19: chr22-33746526; API