16-8847731-A-T

Position:

• chr16-8847731-A-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000303.3(PMM2):​c.647A>T​(p.Asn216Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,658 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. N216D) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PMM2 NM_000303.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.74

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 18 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-8847730-A-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 16-8847731-A-T is Pathogenic according to our data. Variant chr16-8847731-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-8847731-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMM2	NM_000303.3	c.647A>T	p.Asn216Ile	missense_variant	8/8	ENST00000268261.9	NP_000294.1
PMM2	XM_047434215.1	c.398A>T	p.Asn133Ile	missense_variant	6/6		XP_047290171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMM2	ENST00000268261.9	c.647A>T	p.Asn216Ile	missense_variant	8/8	1	NM_000303.3	ENSP00000268261.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460658 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726692

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PMM2-congenital disorder of glycosylation Pathogenic:8

Likely pathogenic, criteria provided, single submitter	clinical testing	Pediatric Metabolic Diseases, Hacettepe University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 22, 2023	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. Experimental studies have shown that this missense change affects PMM2 function (PMID: 9140401, 25355454). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 7707). This missense change has been observed in individuals with PMM2-congenital disorder of glycosylation (PMID: 9140401, 9497260, 11875054, 12905014, 23430838, 25355454). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 216 of the PMM2 protein (p.Asn216Ile). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007707). 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: 12905014). A different missense change at the same codon (p.Asn216Ser) has been reported to be associated with PMM2 -related disorder (PMID: 11058896). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 17, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 02, 2022	Variant summary: PMM2 c.647A>T (p.Asn216Ile) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251180 control chromosomes. c.647A>T has been reported in the literature in individuals affected with Congenital Disorder Of Glycosylation Type 1a. These data indicate that the variant may be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Jun 28, 2022	PS4, PM1, PM2, PM5, PP2, PP3, PP5 -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 17, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D;D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.1	.;H;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-8.6	D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.99
MutPred		0.97		.;Loss of disorder (P = 0.0281);.;
MVP		0.97
MPC		0.023
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.98
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs78290141; hg19: chr16-8941588;