rs199912424
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_133642.5(LARGE1):āc.1229A>Gā(p.Asn410Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000217 in 1,614,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 31)
Exomes š: 0.000023 ( 0 hom. )
Consequence
LARGE1
NM_133642.5 missense
NM_133642.5 missense
Scores
1
3
10
Clinical Significance
Conservation
PhyloP100: 5.77
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 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.18633002).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LARGE1 | NM_133642.5 | c.1229A>G | p.Asn410Ser | missense_variant | 10/15 | ENST00000397394.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LARGE1 | ENST00000397394.8 | c.1229A>G | p.Asn410Ser | missense_variant | 10/15 | 5 | NM_133642.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152116Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251326Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135844
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GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12AN XY: 727244
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152234Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74424
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Muscular dystrophy-dystroglycanopathy type B6 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 03, 2022 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 410 of the LARGE1 protein (p.Asn410Ser). This variant is present in population databases (rs199912424, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with LARGE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 464467). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 03, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;.;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Pathogenic
D
Sift4G
Uncertain
T;D;D;T;T
Polyphen
0.17
.;.;.;B;B
Vest4
0.47, 0.48
MVP
MPC
0.44
ClinPred
T
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at