rs151319324

Positions:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PM1PM5BP4_StrongBS2

The NM_000303.3(PMM2):c.713G>A(p.Arg238His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000402 in 1,613,530 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R238G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00040 ( 2 hom. )

Consequence

PMM2
NM_000303.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:9B:2O:1

Conservation

PhyloP100: 1.94

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a helix (size 11) in uniprot entity PMM2_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000303.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

BP4

Computational evidence support a benign effect (MetaRNN=0.029460818).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMM2	NM_000303.3 linkuse as main transcript	c.713G>A	p.Arg238His	missense_variant	8/8	ENST00000268261.9	NP_000294.1
PMM2	XM_047434215.1 linkuse as main transcript	c.464G>A	p.Arg155His	missense_variant	6/6		XP_047290171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMM2	ENST00000268261.9 linkuse as main transcript	c.713G>A	p.Arg238His	missense_variant	8/8	1	NM_000303.3	ENSP00000268261	P1	O15305-1
	ENST00000567942.1 linkuse as main transcript	n.283C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.000414

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000574

AC:

144

AN:

250978

Hom.:

AF XY:

0.000597

AC XY:

AN XY:

135690

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00486

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.0000468

Gnomad NFE exome

AF:

0.000704

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000401

AC:

586

AN:

1461332

Hom.:

Cov.:

AF XY:

0.000407

AC XY:

296

AN XY:

726996

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00524

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000290

Gnomad4 FIN exome

AF:

0.0000376

Gnomad4 NFE exome

AF:

0.000326

Gnomad4 OTH exome

AF:

0.000662

GnomAD4 genome

AF:

0.000414

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000544

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000736

Hom.:

Bravo

AF:

0.000442

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000593

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:9Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

PMM2-congenital disorder of glycosylation

Pathogenic:1Uncertain:2Benign:2Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Morava/Kozicz Lab, Department of Clinical Genomics, Mayo Clinic	Mar 18, 2022	Missense variants in nearby residues reported in the HGMD in individuals with PMM2-CD (Stenson et al, 2014) (PM1). Observed with pathogenic variant on the opposite allele (in trans) in this patient (PM3). Parents are heterozygotes. The mode of inheritance is in line with previous reports (AR). The majority of missense variants in this gene are considered pathogenic (Stenson et al 2014). In silico analysis, which includes protein predictors and evolutionary conservation supports a deleterious effect (PP3). Observed in 0.0549 % (155/282362 alleles) in large population cohorts (Lek et al, 2016). Phenotype of the patient is in line with previously described PMM2-CDG patients (PP4). Other clinical tests stronly support PMM2-CDG diagnosis and indicate the variant is pathogenic. According to the guidelines of ACMG we classify this variant as likely pathogenic (2 PM and 2 PP). -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	Variant classified as Likely pathogenic and reported on 10-26-2020 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 17, 2020	- -

not provided

Uncertain:6

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 23, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9497260, 37372416, 25681648, 10066032, 27231023, 36099812, 34652821, 37224763, 34132027) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 24, 2015	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 19, 2022

Variant summary: PMM2 c.713G>A (p.Arg238His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00057 in 250978 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PMM2 causing Congenital Disorder Of Glycosylation Type 1a (0.00057 vs 0.0056), allowing no conclusion about variant significance. c.713G>A has been reported in the literature in individuals affected with Charcot-Marie-Tooth or Oral-facial-digital syndrome. These reports do not provide unequivocal conclusions about association of the variant with Congenital Disorder Of Glycosylation Type 1a. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely pathogenic n=2, VUS n=4, likely benign n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

D;D;.

Eigen

Benign

0.046

Eigen_PC

Benign

-0.025

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.029

T;T;T

MetaSVM

Uncertain

0.62

MutationAssessor

Uncertain

2.4

.;M;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-2.2

N;D;N

REVEL

Uncertain

0.49

Sift

Benign

0.47

T;T;D

Sift4G

Benign

0.60

T;T;T

Polyphen

0.93

.;P;.

Vest4

0.42

MVP

0.91

MPC

0.021

ClinPred

0.084

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.30

gMVP

0.74

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