rs34258285

Positions:

chr16-8813057-A-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000303.3(PMM2):c.590A>C(p.Glu197Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.023 in 1,613,114 control chromosomes in the GnomAD database, including 535 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 58 hom., cov: 33)

Exomes 𝑓: 0.023 ( 477 hom. )

Consequence

PMM2
NM_000303.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 2.25

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 Benign. Variant got -18 ACMG points.

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0045259).

BP6

Variant 16-8813057-A-C is Benign according to our data. Variant chr16-8813057-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 92803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-8813057-A-C is described in Lovd as [Benign]. Variant chr16-8813057-A-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0201 (3067/152354) while in subpopulation NFE AF= 0.0281 (1909/68028). AF 95% confidence interval is 0.027. There are 58 homozygotes in gnomad4. There are 1505 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 58 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMM2	NM_000303.3 linkuse as main transcript	c.590A>C	p.Glu197Ala	missense_variant	7/8	ENST00000268261.9	NP_000294.1
PMM2	XM_047434215.1 linkuse as main transcript	c.341A>C	p.Glu114Ala	missense_variant	5/6		XP_047290171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMM2	ENST00000268261.9 linkuse as main transcript	c.590A>C	p.Glu197Ala	missense_variant	7/8	1	NM_000303.3	ENSP00000268261	P1	O15305-1

Frequencies

GnomAD3 genomes

AF:

0.0201

AC:

3067

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00408

Gnomad AMI

AF:

0.0515

Gnomad AMR

AF:

0.0209

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.0490

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0281

Gnomad OTH

AF:

0.0210

GnomAD3 exomes

AF:

0.0200

AC:

5018

AN:

251472

Hom.:

AF XY:

0.0200

AC XY:

2719

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00320

Gnomad AMR exome

AF:

0.0132

Gnomad ASJ exome

AF:

0.0117

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00487

Gnomad FIN exome

AF:

0.0506

Gnomad NFE exome

AF:

0.0265

Gnomad OTH exome

AF:

0.0220

GnomAD4 exome

AF:

0.0233

AC:

33972

AN:

1460760

Hom.:

477

Cov.:

AF XY:

0.0230

AC XY:

16723

AN XY:

726750

show subpopulations

Gnomad4 AFR exome

AF:

0.00362

Gnomad4 AMR exome

AF:

0.0151

Gnomad4 ASJ exome

AF:

0.0117

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00521

Gnomad4 FIN exome

AF:

0.0507

Gnomad4 NFE exome

AF:

0.0257

Gnomad4 OTH exome

AF:

0.0191

GnomAD4 genome

AF:

0.0201

AC:

3067

AN:

152354

Hom.:

Cov.:

AF XY:

0.0202

AC XY:

1505

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00406

Gnomad4 AMR

AF:

0.0208

Gnomad4 ASJ

AF:

0.0101

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.00393

Gnomad4 FIN

AF:

0.0490

Gnomad4 NFE

AF:

0.0281

Gnomad4 OTH

AF:

0.0208

Alfa

AF:

0.0252

Hom.:

119

Bravo

AF:

0.0173

TwinsUK

AF:

0.0227

AC:

ALSPAC

AF:

0.0270

AC:

104

ESP6500AA

AF:

0.00478

AC:

ESP6500EA

AF:

0.0255

AC:

219

ExAC

AF:

0.0193

AC:

2343

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0259

EpiControl

AF:

0.0258

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 02, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1.9% in ExAC, 5% Finnish, 36 homozygotes -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 18, 2012	- -

PMM2-congenital disorder of glycosylation

Benign:6

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign, for Congenital disorder of glycosylation, type IA, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. BS3-Supporting => BS3 downgraded in strength to supporting (PMID:21541725). -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 05, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PMM2: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.020

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.78

D;D;.

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.74

T;T;T

MetaRNN

Benign

0.0045

T;T;T

MetaSVM

Uncertain

0.36

MutationAssessor

Benign

1.8

.;L;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.2

D;D;D

REVEL

Uncertain

0.58

Sift

Benign

0.079

T;T;T

Sift4G

Benign

0.096

T;T;T

Polyphen

0.0020

.;B;.

Vest4

0.085

MPC

0.0080

ClinPred

0.021

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.43

gMVP

0.79

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