22-33316156-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_133642.5(LARGE1):​c.1380C>A​(p.Phe460Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

LARGE1
NM_133642.5 missense

Scores

3
8
7

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.03
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LARGE1NM_133642.5 linkc.1380C>A p.Phe460Leu missense_variant Exon 11 of 15 ENST00000397394.8 NP_598397.1 O95461-1X5DR28

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LARGE1ENST00000397394.8 linkc.1380C>A p.Phe460Leu missense_variant Exon 11 of 15 5 NM_133642.5 ENSP00000380549.2 O95461-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461852
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Uncertain
0.040
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.78
.;.;.;D;D;.
Eigen
Benign
0.12
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.88
D;D;D;.;D;D
M_CAP
Benign
0.011
T
MetaRNN
Uncertain
0.56
D;D;D;D;D;D
MetaSVM
Benign
-0.96
T
PrimateAI
Pathogenic
0.87
D
PROVEAN
Uncertain
-4.2
.;.;.;D;D;D
REVEL
Benign
0.19
Sift
Benign
0.18
.;.;.;T;T;T
Sift4G
Benign
0.16
T;T;T;T;T;T
Polyphen
0.10, 0.30
.;.;.;B;B;B
Vest4
0.94, 0.94, 0.94
MutPred
0.60
.;.;.;Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);.;
MVP
0.68
MPC
1.6
ClinPred
0.97
D
GERP RS
5.3
Varity_R
0.32
gMVP
0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-33712142; API