rs1250351189
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001077365.2(POMT1):βc.485delβ(p.Phe162SerfsTer10) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000403 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000020 ( 0 hom., cov: 33)
Exomes π: 0.000042 ( 0 hom. )
Consequence
POMT1
NM_001077365.2 frameshift
NM_001077365.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.91
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 Pathogenic. Variant got 18 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 9-131508963-AT-A is Pathogenic according to our data. Variant chr9-131508963-AT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 505535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-131508963-AT-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POMT1 | NM_001077365.2 | c.485del | p.Phe162SerfsTer10 | frameshift_variant | 6/20 | ENST00000402686.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POMT1 | ENST00000402686.8 | c.485del | p.Phe162SerfsTer10 | frameshift_variant | 6/20 | 1 | NM_001077365.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152134Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251442Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135900
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GnomAD4 exome AF: 0.0000424 AC: 62AN: 1461780Hom.: 0 Cov.: 32 AF XY: 0.0000413 AC XY: 30AN XY: 727190
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Walker-Warburg congenital muscular dystrophy;C1836373:Autosomal recessive limb-girdle muscular dystrophy type 2K;C5436962:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 07, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 505535). This variant has not been reported in the literature in individuals affected with POMT1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Phe162Serfs*10) in the POMT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POMT1 are known to be pathogenic (PMID: 12369018, 15637732, 16575835). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 14, 2022 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Identified in the heterozygous state through genome sequencing in published literature; however, no clinical information or information on whether a second variant was identified was provided (Ceyhan-Birsoy et al., 2019; Hou et al., 2020); This variant is associated with the following publications: (PMID: 31980526, 30609409) - |
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 15, 2024 | - - |
Walker-Warburg congenital muscular dystrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 02, 2017 | The p.Phe162SerfsX10 (NM007171.3 c.485delT) variant in POMT1 has not been report ed in individuals with POMT1-related muscular dystrophy-dystroglycanopathies. Th is variant has been identified in 1/8254 of European chromosomes by the NHLBI Ex ome Sequencing Project (http://evs.gs.washington.edu/EVS). Although this variant has been seen in the general population, its frequency is low enough to be cons istent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 162 and leads to a premature termination codon 10 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the POMT1 gene has been associated with POMT1-related muscu lar dystrophy-dystroglycanopathies. In summary, although additional studies are required to fully establish a null effect, the p.Phe162SerfsX10 variant is likel y pathogenic for POMT1-related muscular dystrophy-dystroglycanopathies in an aut osomal recessive manner based upon its predicted impact on protein function. - |
Computational scores
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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