rs201073763
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_001077365.2(POMT1):āc.789G>Cā(p.Leu263Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,614,070 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 0.00019 ( 0 hom., cov: 33)
Exomes š: 0.00024 ( 0 hom. )
Consequence
POMT1
NM_001077365.2 missense
NM_001077365.2 missense
Scores
10
7
Clinical Significance
Conservation
PhyloP100: 3.08
Genes affected
POMT1 (HGNC:9202): (protein O-mannosyltransferase 1) The protein encoded by this gene is an O-mannosyltransferase that requires interaction with the product of the POMT2 gene for enzymatic function. The encoded protein is found in the membrane of the endoplasmic reticulum. Defects in this gene are a cause of Walker-Warburg syndrome (WWS) and limb-girdle muscular dystrophy type 2K (LGMD2K). Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.37188768).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POMT1 | NM_001077365.2 | c.789G>C | p.Leu263Phe | missense_variant | 9/20 | ENST00000402686.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POMT1 | ENST00000402686.8 | c.789G>C | p.Leu263Phe | missense_variant | 9/20 | 1 | NM_001077365.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000191 AC: 29AN: 152198Hom.: 0 Cov.: 33
GnomAD3 genomes
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GnomAD3 exomes AF: 0.000123 AC: 31AN: 251474Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135912
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GnomAD4 exome AF: 0.000237 AC: 346AN: 1461872Hom.: 0 Cov.: 35 AF XY: 0.000249 AC XY: 181AN XY: 727238
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GnomAD4 genome ? AF: 0.000191 AC: 29AN: 152198Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13AN XY: 74364
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:6
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 02, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 05, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 20, 2022 | Described as a non-pathogenic variant in a cohort of individuals with Walker-Warburg syndrome (van Reeuwijk et al., 2006); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17878207, 16575835, 30564623) - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 23, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2K Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Autosomal recessive limb-girdle muscular dystrophy type 2K;C4284790:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1;C5436962:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Walker-Warburg congenital muscular dystrophy;C1836373:Autosomal recessive limb-girdle muscular dystrophy type 2K;C5436962:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2022 | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 285 of the POMT1 protein (p.Leu285Phe). This variant is present in population databases (rs201073763, gnomAD 0.02%). This missense change has been observed in individual(s) with Walker-Warburg syndrome. This publication describes this variant as a polymorphism (PMID: 16575835). ClinVar contains an entry for this variant (Variation ID: 288794). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POMT1 protein function. 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. - |
Pyridoxine-dependent epilepsy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | May 19, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;.;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D;N
REVEL
Uncertain
Sift
Benign
T;T;T;T;T;T;T
Sift4G
Benign
T;T;T;T;T;T;D
Polyphen
0.49, 1.0
.;P;.;.;D;P;.
Vest4
MutPred
0.59
.;.;.;.;Gain of helix (P = 0.1736);.;.;
MVP
MPC
0.93
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
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Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at