rs398123311

Variant names:

• chr16-8847770-A-C
• rs398123311
• NM_000303.3:c.686A>C

Your query was ambiguous. Multiple possible variants found:

• chr16-8847770-A-C
• chr16-8847770-A-G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_000303.3(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). 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 NM_000303.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 5.45
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• congenital disorder of glycosylation type I

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• PMM2-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, ClinGen

ENSG00000260350 (HGNC:58482):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000303.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 89 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: -1.3872 (below the threshold of 3.09). Trascript score misZ: -1.8083 (below the threshold of 3.09). GenCC associations: The gene is linked to PMM2-congenital disorder of glycosylation, congenital disorder of glycosylation type I.
• 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 VariationId is 92806.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMM2	ENST00000268261.9	c.686A>C	p.Tyr229Ser	missense_variant	Exon 8 of 8	1	NM_000303.3	ENSP00000268261.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

PMM2-congenital disorder of glycosylation Pathogenic:2

Mar 22, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Jun 12, 2013

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;.
PhyloP100		5.5
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
Mutation Taster		=7/93	disease causing

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

Other links and lift over

dbSNP: rs398123311; hg19: chr16-8941627;