rs781610241

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_000303.3(PMM2):c.426T>G(p.Ile142Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000306 in 1,569,972 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I142V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

PMM2
NM_000303.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -0.0230

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]

PMM2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000303.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3323856).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMM2	NM_000303.3 linkuse as main transcript	c.426T>G	p.Ile142Met	missense_variant	5/8	ENST00000268261.9
PMM2	XM_047434215.1 linkuse as main transcript	c.177T>G	p.Ile59Met	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMM2	ENST00000268261.9 linkuse as main transcript	c.426T>G	p.Ile142Met	missense_variant	5/8	1	NM_000303.3	P1	O15305-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000209

AC:

AN:

191302

Hom.:

AF XY:

0.00000980

AC XY:

AN XY:

102086

show subpopulations

Gnomad AFR exome

AF:

0.0000847

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000385

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000296

AC:

AN:

1417752

Hom.:

Cov.:

AF XY:

0.0000313

AC XY:

AN XY:

701924

show subpopulations

Gnomad4 AFR exome

AF:

0.0000308

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000369

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000100

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000257

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

PMM2-congenital disorder of glycosylation

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 30, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 20, 2022	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 142 of the PMM2 protein (p.Ile142Met). This variant is present in population databases (rs781610241, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with PMM2-related conditions. ClinVar contains an entry for this variant (Variation ID: 495798). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 25, 2016

Variant Summary: This PMM2 variant affects a non-conserved nucleotide, resulting in an amino acid change from Ile to Met. 3/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). Functional studies on this variant have not been carried out. This variant was found in 2/31948 control chromosomes at a frequency of 0.0000626, which does not exceed the maximal allele frequency of a pathogenic PMM2 variant (0.0055902). This variant has been reported in one patient with intellectual disability without a second pathogenic allele (Redin_2014) and authors predict the variant to be possibly benign. Because of limited clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Uncertain

0.042

BayesDel_noAF

Uncertain

0.020

Cadd

Benign

Dann

Benign

0.97

DEOGEN2

Uncertain

0.53

D;D

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.88

D;D

M_CAP

Uncertain

0.098

MetaRNN

Benign

0.33

T;T

MetaSVM

Uncertain

0.38

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.70

N;N

Sift

Benign

0.12

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.035

.;B

Vest4

0.40

MutPred

0.40

.;Gain of disorder (P = 0.0388);

MVP

0.87

MPC

0.0079

ClinPred

0.032

GERP RS

0.14

Varity_R

0.20

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over