16-8804793-C-T

Position:

• chr16-8804793-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000303.3(PMM2):​c.205C>T​(p.Pro69Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000246 in 1,461,054 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: PMM2 NM_000303.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.94

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849
• PP5: Variant 16-8804793-C-T is Pathogenic according to our data. Variant chr16-8804793-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-8804793-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMM2	NM_000303.3	c.205C>T	p.Pro69Ser	missense_variant	3/8	ENST00000268261.9	NP_000294.1
PMM2	XM_047434215.1	c.7-1523C>T		intron_variant			XP_047290171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMM2	ENST00000268261.9	c.205C>T	p.Pro69Ser	missense_variant	3/8	1	NM_000303.3	ENSP00000268261.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461054 Hom.: 0 Cov.: 29 AF XY: 0.0000275 AC XY: 20 AN XY: 726866

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000324

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PMM2-congenital disorder of glycosylation Pathogenic:6

Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Sep 24, 2024	ACMG codes: PS3_Strong, PS4_Strong, PM3_Strong, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 14, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 13, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 24, 2016	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 15, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 69 of the PMM2 protein (p.Pro69Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of PMM2-related conditions (PMID: 22801829, 31391289). 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. ClinVar contains an entry for this variant (Variation ID: 371307). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 25, 2024

In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31391289, 19862844, 10527672, 12357336, 15844218, 33413482, 34782856, 22801829, 11156536, 37224763, 32635232) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	20
DANN	Benign	0.31
DEOGEN2	Uncertain	0.49	T;D
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.073
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	0.39	.;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.97	N;N
REVEL	Uncertain	0.50
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.028	.;B
Vest4		0.78
MutPred		0.87		.;Gain of sheet (P = 0.1208);
MVP		0.87
MPC		0.010
ClinPred		0.90	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.47		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.47		Position offset: -26

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs769648248; hg19: chr16-8898650;