rs104894531

Positions:

• chr16-8847753-C-G
• chr16-8847753-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Strong PP5

The NM_000303.3(PMM2):​c.669C>G​(p.Asp223Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D223N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PMM2 NM_000303.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.04

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PS1: Transcript NM_000303.3 (PMM2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 2677894
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain 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 chr16-8847751-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2429140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 16-8847753-C-G is Pathogenic according to our data. Variant chr16-8847753-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 7714.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMM2	NM_000303.3	c.669C>G	p.Asp223Glu	missense_variant	8/8	ENST00000268261.9
PMM2	XM_047434215.1	c.420C>G	p.Asp140Glu	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMM2	ENST00000268261.9	c.669C>G	p.Asp223Glu	missense_variant	8/8	1	NM_000303.3	P1
	ENST00000567942.1	n.327G>C		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

PMM2-congenital disorder of glycosylation Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Pathogenic	3.9	.;H;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.75	.;P;.
Vest4		0.98
MutPred		0.95		.;Gain of disorder (P = 0.1362);.;
MVP		0.92
MPC		0.017
ClinPred		0.99	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.86

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: rs104894531; hg19: chr16-8941610;