chr16-8797883-A-G

Position:

• chr16-8797883-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000303.3(PMM2):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,459,240 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: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PMM2 NM_000303.3 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.46

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-8797883-A-G is Pathogenic according to our data. Variant chr16-8797883-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-8797883-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMM2	NM_000303.3	c.1A>G	p.Met1?	start_lost	1/8	ENST00000268261.9	NP_000294.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMM2	ENST00000268261.9	c.1A>G	p.Met1?	start_lost	1/8	1	NM_000303.3	ENSP00000268261.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000413 AC: 1 AN: 242326 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 131944

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000914

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1459240 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 725768

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: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PMM2-congenital disorder of glycosylation Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 23, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 31, 2020	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Sep 12, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 25, 2024	This sequence change affects the initiator methionine of the PMM2 mRNA. The next in-frame methionine is located at codon 28. This variant is present in population databases (rs786204591, gnomAD 0.0009%). Disruption of the initiator codon has been observed in individual(s) with PMM2-congenital disorder of glycosylation (PMID: 18948042). ClinVar contains an entry for this variant (Variation ID: 188965). This variant disrupts the p.Gly15 amino acid residue in PMM2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12626389, 28454995; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Benign	19
DANN	Benign	0.91
DEOGEN2	Uncertain	0.49	T;.
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
PROVEAN	Benign	-1.1	N;N
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.067	T;T
Polyphen		0.71	P;.
Vest4		0.92
MutPred		1.0		Loss of glycosylation at P4 (P = 0.0894);Loss of glycosylation at P4 (P = 0.0894);
MVP		0.97
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.78

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: rs786204591; hg19: chr16-8891740; COSMIC: COSV99191108; COSMIC: COSV99191108;