rs146303063
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_032237.5(POMK):c.373A>T(p.Met125Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,614,076 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00015 ( 1 hom. )
Consequence
POMK
NM_032237.5 missense
NM_032237.5 missense
Scores
4
9
6
Clinical Significance
Conservation
PhyloP100: 8.39
Genes affected
POMK (HGNC:26267): (protein O-mannose kinase) This gene encodes a protein that may be involved in the presentation of the laminin-binding O-linked carbohydrate chain of alpha-dystroglycan (a-DG), which forms transmembrane linkages between the extracellular matrix and the exoskeleton. Some pathogens use this O-linked carbohydrate unit for host entry. Loss of function compound heterozygous mutations in this gene were found in a human patient affected by the Walker-Warburg syndrome (WWS) phenotype. Mice lacking this gene contain misplaced neurons (heterotopia) in some regions of the brain, possibly from defects in neuronal migration. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.029518694).
BP6
Variant 8-43122197-A-T is Benign according to our data. Variant chr8-43122197-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436703.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POMK | NM_032237.5 | c.373A>T | p.Met125Leu | missense_variant | 5/5 | ENST00000331373.10 | NP_115613.1 | |
POMK | NM_001277971.2 | c.373A>T | p.Met125Leu | missense_variant | 4/4 | NP_001264900.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POMK | ENST00000331373.10 | c.373A>T | p.Met125Leu | missense_variant | 5/5 | 2 | NM_032237.5 | ENSP00000331258.5 |
Frequencies
GnomAD3 genomes AF: 0.000177 AC: 27AN: 152206Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000306 AC: 77AN: 251446Hom.: 1 AF XY: 0.000302 AC XY: 41AN XY: 135890
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GnomAD4 exome AF: 0.000151 AC: 221AN: 1461870Hom.: 1 Cov.: 33 AF XY: 0.000160 AC XY: 116AN XY: 727236
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GnomAD4 genome AF: 0.000177 AC: 27AN: 152206Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14AN XY: 74360
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 28, 2015 | - - |
POMK-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 25, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 12;C4015184:Limb-girdle muscular dystrophy due to POMK deficiency Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 06, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;T;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;D;.
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;N;D
REVEL
Pathogenic
Sift
Pathogenic
.;D;D
Sift4G
Uncertain
D;D;D
Polyphen
P;.;P
Vest4
MutPred
Loss of catalytic residue at M125 (P = 0.0391);Loss of catalytic residue at M125 (P = 0.0391);Loss of catalytic residue at M125 (P = 0.0391);
MVP
MPC
0.23
ClinPred
T
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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