rs104894530

Variant names:

• chr16-8811080-G-A
• NM_000303.3:c.349G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-8811080-G-A
• chr16-8811080-G-C
• chr16-8811080-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000303.3(PMM2):​c.349G>A​(p.Gly117Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,395,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PMM2 NM_000303.3 missense, splice_region
• Scores: Splicing: ADA: 0.9764
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.79

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 Uncertain_significance. Variant got 5 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMM2	NM_000303.3	c.349G>A	p.Gly117Ser	missense_variant, splice_region_variant	Exon 5 of 8	ENST00000268261.9	NP_000294.1
PMM2	XM_047434215.1	c.100G>A	p.Gly34Ser	missense_variant, splice_region_variant	Exon 3 of 6		XP_047290171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMM2	ENST00000268261.9	c.349G>A	p.Gly117Ser	missense_variant, splice_region_variant	Exon 5 of 8	1	NM_000303.3	ENSP00000268261.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1395586 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 690788

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: 0.00000187

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	.;H
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.011	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	.;D
Vest4		0.95
MutPred		0.96		.;Gain of phosphorylation at G117 (P = 0.069);
MVP		0.98
MPC		0.047
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-8904937;