chr16-8801823-T-C
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP5
The NM_000303.3(PMM2):āc.91T>Cā(p.Phe31Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000987 in 1,610,454 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. F31F) has been classified as Likely benign.
Frequency
Genomes: š 0.000046 ( 0 hom., cov: 33)
Exomes š: 0.00010 ( 0 hom. )
Consequence
PMM2
NM_000303.3 missense
NM_000303.3 missense
Scores
3
7
7
Clinical Significance
Conservation
PhyloP100: 5.81
Genes affected
PMM2 (HGNC:9115): (phosphomannomutase 2) The protein encoded by this gene catalyzes the isomerization of mannose 6-phosphate to mannose 1-phosphate, which is a precursor to GDP-mannose necessary for the synthesis of dolichol-P-oligosaccharides. Mutations in this gene have been shown to cause defects in glycoprotein biosynthesis, which manifests as carbohydrate-deficient glycoprotein syndrome type I. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM1
In a chain Phosphomannomutase 2 (size 244) in uniprot entity PMM2_HUMAN there are 200 pathogenic changes around while only 6 benign (97%) in NM_000303.3
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-8801823-T-C is Pathogenic according to our data. Variant chr16-8801823-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 425093.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=3}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMM2 | NM_000303.3 | c.91T>C | p.Phe31Leu | missense_variant | 2/8 | ENST00000268261.9 | |
PMM2 | XM_047434215.1 | c.-82T>C | 5_prime_UTR_variant | 1/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMM2 | ENST00000268261.9 | c.91T>C | p.Phe31Leu | missense_variant | 2/8 | 1 | NM_000303.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152220Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000766 AC: 19AN: 248014Hom.: 0 AF XY: 0.0000894 AC XY: 12AN XY: 134158
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GnomAD4 exome AF: 0.000104 AC: 152AN: 1458234Hom.: 0 Cov.: 30 AF XY: 0.000112 AC XY: 81AN XY: 725422
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152220Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74364
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
PMM2-congenital disorder of glycosylation Pathogenic:2Uncertain:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 31 of the PMM2 protein (p.Phe31Leu). This variant is present in population databases (rs749720760, gnomAD 0.02%). This missense change has been observed in individual(s) with PMM2-congenital disorder of glycosylation (PMM2-CDG) (PMID: 28122681). ClinVar contains an entry for this variant (Variation ID: 425093). 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 expected to disrupt PMM2 protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 03, 2021 | NM_000303.2(PMM2):c.91T>C(F31L) is a missense variant classified as a variant of uncertain significance in the context of congenital disorder of glycosylation type Ia. F31L has been observed in a case with relevant disease (PMID 28122681). Functional assessments of this variant are not available in the literature. F31L has been observed in population frequency databases (gnomAD: AMR 0.02%). In summary, there is insufficient evidence to classify NM_000303.2(PMM2):c.91T>C(F31L) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 22, 2024 | - - |
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 30, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 18, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 15, 2022 | Variant summary: PMM2 c.91T>C (p.Phe31Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.7e-05 in 248014 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PMM2 causing Congenital Disorder Of Glycosylation Type 1a (7.7e-05 vs 0.0056), allowing no conclusion about variant significance. c.91T>C has been reported in the literature as a novel variant in one individual affected with Congenital Disorder of Glycosylation Type 1a with elevated levels of asialotransferrin and disialotransferrin, and low tetrasialotransferrin (Teneiji_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T;T;T
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;N
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
0.74
.;P;.
Vest4
MutPred
0.63
.;Loss of methylation at K26 (P = 0.0973);Loss of methylation at K26 (P = 0.0973);
MVP
MPC
0.021
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
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