dbSNP rs80338701: PMM2:p.Phe119Leu (chr16-8811088-C-A) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is . The variant received 18 classification points (ACMG Germline Pathogenicity v2019): 18P and 0B. PS1PS3PM1PM2PP3_ModeratePP5_Strong

The NM_000303.3(PMM2):c.357C>A (p.Phe119Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000352 (AC=55) in the gnomAD database across 1,561,744 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000344. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000399673: In vitro functional studies in E. coli BL21 (DE3) cells demonstrated that the p.Phe119Leu variant results in 25% residual enzyme activity, reduced protein activity and stability, and altered protein quaternary structure as compared to wild type (Kjaergaard et al. 1999" and additional evidence is available in ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.F119= (synonymous): Likely_benign (ClinVar VariationId 1079128, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

Frequency

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

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

PMM2
NM_000303.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:25O:1

Conservation

PhyloP100: 1.24

Publications

74 publications found

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 Gene-Disease associations (from GenCC):

congenital disorder of glycosylation type I
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women's Health
PMM2-congenital disorder of glycosylation
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, PanelApp Australia, Orphanet
hyperinsulinemic hypoglycemia with polycystic kidney disease
Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, ClinGen

PMM2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000303.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 points.

PS1

Same AA change, 1-star ClinVar pathogenic — strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 1 star).

PS3

Well-established functional study supports damaging effect (PS3); SCV000399673: In vitro functional studies in E. coli BL21 (DE3) cells demonstrated that the p.Phe119Leu variant results in 25% residual enzyme activity, reduced protein activity and stability, and altered protein quaternary structure as compared to wild type (Kjaergaard et al. 1999; Andreotti et al. 2013).; SCV000680023: Functional studies show this variant in compound heterozygous state weakens quaternary structure, destabilises the protein and reduces enzyme activity (Andreotti. et al., (2013) and Noelle et al., (2005)).; SCV000833921: Experimental studies have shown that this missense change affects PMM2 function (PMID: 24498599, 26488408, 27053713).; SCV000920013: The most pronounced variant effect results in 10%-<30% of normal activity.; SCV001818601: Functional studies demonstrate a damaging effect with disruption of dimerization and significantly reduced enzyme activity (Andreotti et al., 2013);

PM1

Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 8 pathogenic, 0 benign (OR vs. background: 85.0).

PM2

Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000344 — very rare for AR gene (base 0.001, raised to 0.0049 by highest known P/LP ClinVar AF 0.0049) — PM2 moderate.

PP3

Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).

PP5

ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (25/25 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000303.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMM2	NM_000303.3	MANE Select	c.357C>A	p.Phe119Leu	missense	Exon 5 of 8	NP_000294.1	A0A0S2Z4J6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PMM2	ENST00000268261.9	TSL:1 MANE Select	c.357C>A	p.Phe119Leu	missense	Exon 5 of 8	ENSP00000268261.4	O15305-1
PMM2	ENST00000565221.5	TSL:1	n.188C>A		non_coding_transcript_exon	Exon 3 of 6	ENSP00000457932.1	H3BV34
PMM2	ENST00000567697.2	TSL:1	n.3525C>A		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000436

AC:

AN:

183678

AF XY:

0.0000410

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000108

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000348

AC:

AN:

1409566

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

697170

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32156

American (AMR)

AF:

0.00

AC:

AN:

39206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25442

East Asian (EAS)

AF:

0.00

AC:

AN:

37394

South Asian (SAS)

AF:

0.00

AC:

AN:

80972

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50072

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.0000444

AC:

AN:

1080330

Other (OTH)

AF:

0.0000172

AC:

AN:

58294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41430

American (AMR)

AF:

0.0000655

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000891

Hom.:

Bravo

AF:

0.0000189

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

PMM2-congenital disorder of glycosylation (16)

not provided (8)

Inborn genetic diseases (1)

PMM2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

PhyloP100

1.2

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-5.8

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Varity_R

0.97

gMVP

0.93

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over