chr16-8847797-G-C

Position:

chr16-8847797-G-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000268261.9(PMM2):c.713G>C(p.Arg238Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R238C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

PMM2
ENST00000268261.9 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

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:

PMM2 (HGNC:):

PMM2 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 20 ACMG points.

PS1

Transcript ENST00000268261.9 (PMM2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in ENST00000268261.9

PM2

Very rare variant in population databases, with high coverage;

PM5

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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.947

PP5

Variant 16-8847797-G-C is Pathogenic according to our data. Variant chr16-8847797-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1333592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMM2	NM_000303.3 linkuse as main transcript	c.713G>C	p.Arg238Pro	missense_variant	8/8	ENST00000268261.9	NP_000294.1	O15305-1A0A0S2Z4J6Q59F02
PMM2	XM_047434215.1 linkuse as main transcript	c.464G>C	p.Arg155Pro	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>C	p.Arg238Pro	missense_variant	8/8	1	NM_000303.3	ENSP00000268261.4		O15305-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152198

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250978

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135690

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461332

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726998

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

PMM2-congenital disorder of glycosylation

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 13, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 16, 2022	ClinVar contains an entry for this variant (Variation ID: 1333592). For these reasons, this variant has been classified as Pathogenic. 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. This missense change has been observed in individual(s) with congenital disorder of glycosylation Ia (PMID: 10066032, 25681648). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs151319324, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 238 of the PMM2 protein (p.Arg238Pro). -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PMM2 related disorder (PMID:9497260, PS1_P). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 25681648, PM3_M). A different missense change at the same codon has been reported to be associated with PMM2 related disorder (PMID:11058895, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.723, PP3_P). A missense variant is a common mechanism associated with Congenital disorder of glycosylation (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.78

D;D;.

Eigen

Benign

0.12

Eigen_PC

Benign

0.037

FATHMM_MKL

Benign

0.53

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.95

D;D;D

MetaSVM

Uncertain

0.69

MutationAssessor

Uncertain

2.4

.;M;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-2.8

D;D;D

REVEL

Pathogenic

0.72

Sift

Benign

0.22

T;T;T

Sift4G

Benign

0.37

T;T;T

Polyphen

0.97

.;D;.

Vest4

0.92

MutPred

0.87

.;Loss of helix (P = 0.0558);.;

MVP

0.91

MPC

0.033

ClinPred

0.92

GERP RS

2.9

Varity_R

0.94

gMVP

0.94

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