16-8812994-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_ModeratePM1PM2PP3_StrongPP5_Moderate

The NM_000303.3(PMM2):​c.527G>T​(p.Gly176Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

Frequency

Genomes: not found (cov: 33)

Consequence

PMM2
NM_000303.3 missense

Scores

16
2
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.48
Variant links:
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 Pathogenic. Variant got 12 ACMG points.

PS1
Transcript NM_000303.3 (PMM2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM1
In a chain Phosphomannomutase 2 (size 244) in uniprot entity PMM2_HUMAN there are 79 pathogenic changes around while only 2 benign (98%) in NM_000303.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.995
PP5
Variant 16-8812994-G-T is Pathogenic according to our data. Variant chr16-8812994-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1328987.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-8812994-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PMM2NM_000303.3 linkc.527G>T p.Gly176Val missense_variant Exon 7 of 8 ENST00000268261.9 NP_000294.1 O15305-1A0A0S2Z4J6Q59F02
PMM2XM_047434215.1 linkc.278G>T p.Gly93Val missense_variant Exon 5 of 6 XP_047290171.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PMM2ENST00000268261.9 linkc.527G>T p.Gly176Val missense_variant Exon 7 of 8 1 NM_000303.3 ENSP00000268261.4 O15305-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

PMM2-congenital disorder of glycosylation Pathogenic:1
Nov 16, 2021
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: PMM2 c.527G>T (p.Gly176Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251478 control chromosomes. c.527G>T has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Congenital Disorder Of Glycosylation Type 1a (example, LeBizec_2005) based on clinical manifestations, confirmed by western blot patterns of serum N-glycoproteins (transferrin, alpha1 transferrin, haptoglobin, alpha1-acid glycoprotein) and deficient cellular activity of phosphomannomutase in leukocytes and/or cultured fibroblasts from forearm biopsy. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal PMM2 enzyme activity activity in an E Coli expression system (LeBizec_2005). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.94
D;D;.
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.99
D;D;D
M_CAP
Pathogenic
0.83
D
MetaRNN
Pathogenic
1.0
D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.1
.;H;.
PrimateAI
Uncertain
0.69
T
PROVEAN
Pathogenic
-8.7
D;D;D
REVEL
Pathogenic
0.99
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
.;D;.
Vest4
0.99
MutPred
0.98
.;Loss of stability (P = 0.0856);.;
MVP
0.95
MPC
0.045
ClinPred
1.0
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-8906851; API