rs749720760

chr16-8801823-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_000303.3(PMM2):c.91T>C(p.Phe31Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000987 in 1,610,454 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. F31F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: PMM2 NM_000303.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:4
• Conservation: PhyloP100: 5.81

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a chain Phosphomannomutase 2 (size 244) in uniprot entity PMM2_HUMAN there are 199 pathogenic changes around while only 6 benign (97%) in NM_000303.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-8801823-T-C is Pathogenic according to our data. Variant chr16-8801823-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 425093.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMM2	NM_000303.3	c.91T>C	p.Phe31Leu	missense_variant	2/8	ENST00000268261.9
PMM2	XM_047434215.1	c.-82T>C		5_prime_UTR_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMM2	ENST00000268261.9	c.91T>C	p.Phe31Leu	missense_variant	2/8	1	NM_000303.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000766 AC: 19 AN: 248014 Hom.: 0 AF XY: 0.0000894 AC XY: 12 AN XY: 134158

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

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: 0.0000988

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000104 AC: 152 AN: 1458234 Hom.: 0 Cov.: 30 AF XY: 0.000112 AC XY: 81 AN XY: 725422

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000246

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: 0.000122

Gnomad4 OTH exome AF: 0.0000997

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74364

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.0000907

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

PMM2-congenital disorder of glycosylation Pathogenic:2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 03, 2021	NM_000303.2(PMM2):c.91T>C(F31L) is a missense variant classified as a variant of uncertain significance in the context of congenital disorder of glycosylation type Ia. F31L has been observed in a case with relevant disease (PMID 28122681). Functional assessments of this variant are not available in the literature. F31L has been observed in population frequency databases (gnomAD: AMR 0.02%). In summary, there is insufficient evidence to classify NM_000303.2(PMM2):c.91T>C(F31L) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 28, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 31 of the PMM2 protein (p.Phe31Leu). This variant is present in population databases (rs749720760, gnomAD 0.02%). This missense change has been observed in individual(s) with PMM2-congenital disorder of glycosylation (PMM2-CDG) (PMID: 28122681). ClinVar contains an entry for this variant (Variation ID: 425093). 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 with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 18, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 30, 2016	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 15, 2022

Variant summary: PMM2 c.91T>C (p.Phe31Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.7e-05 in 248014 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PMM2 causing Congenital Disorder Of Glycosylation Type 1a (7.7e-05 vs 0.0056), allowing no conclusion about variant significance. c.91T>C has been reported in the literature as a novel variant in one individual affected with Congenital Disorder of Glycosylation Type 1a with elevated levels of asialotransferrin and disialotransferrin, and low tetrasialotransferrin (Teneiji_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance and one as likely pathogenic. 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	Pathogenic	0.94
BayesDel_addAF	Benign	-0.00071	T
BayesDel_noAF	Uncertain	0.030
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;D;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.86	D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Pathogenic	0.86	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.1	D;D;N
Sift	Benign	0.44	T;T;T
Sift4G	Benign	0.38	T;T;T
Polyphen		0.74	.;P;.
Vest4		0.40
MutPred		0.63		.;Loss of methylation at K26 (P = 0.0973);Loss of methylation at K26 (P = 0.0973);
MVP		0.96
MPC		0.021
ClinPred		0.27	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.84

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

Other links and lift over

dbSNP: rs749720760; hg19: chr16-8895680;