chr16-8847770-A-C

Position:

• chr16-8847770-A-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1_Moderate PM1 PM2 PP3_Strong PP5

The ENST00000268261.9(PMM2):​c.686A>C​(p.Tyr229Ser) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Synonymous variant affecting the same amino acid position (i.e. Y229Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PMM2 ENST00000268261.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.45

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 11 ACMG points.

• PS1: Transcript ENST00000268261.9 (PMM2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in ENST00000268261.9
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant 16-8847770-A-C is Pathogenic according to our data. Variant chr16-8847770-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 92806.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr16-8847770-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMM2	NM_000303.3	c.686A>C	p.Tyr229Ser	missense_variant	8/8	ENST00000268261.9	NP_000294.1
PMM2	XM_047434215.1	c.437A>C	p.Tyr146Ser	missense_variant	6/6		XP_047290171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMM2	ENST00000268261.9	c.686A>C	p.Tyr229Ser	missense_variant	8/8	1	NM_000303.3	ENSP00000268261	P1
	ENST00000567942.1	n.310T>G		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

PMM2-congenital disorder of glycosylation Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Mar 22, 2024

Variant summary: PMM2 c.686A>C (p.Tyr229Ser) 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 was absent in 251276 control chromosomes (gnomAD). c.686A>C has been reported in the literature in individuals affected with Congenital Disorder Of Glycosylation Type 1a (Mattijs_1998, Kondo_1999, Dang Do_2023). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9497260, 10066032, 36719165). ClinVar contains an entry for this variant (Variation ID: 92806). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 12, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	23
DANN	Benign	0.93
DEOGEN2	Pathogenic	0.84	D;D;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	1.7	.;L;.
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.56	.;P;.
Vest4		0.78
MutPred		0.89		.;Gain of disorder (P = 0.0022);.;
MVP		0.92
MPC		0.0090
ClinPred		0.93	D
GERP RS		4.1
Varity_R		0.91
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs398123311; hg19: chr16-8941627;