rs80338703

Variant names:

• chr16-8811146-G-A
• rs80338703
• NM_000303.3:c.415G>A

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000303.3(PMM2):​c.415G>A​(p.Glu139Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,423,654 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002011979: Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID:15844218)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PMM2 NM_000303.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 5.49
• Publications: 33 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: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• hyperinsulinemic hypoglycemia with polycystic kidney disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002011979: Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 15844218).; SCV003443499: Experimental studies have shown that this missense change affects PMM2 function (PMID: 10571956).; SCV000568192: Functional studies demonstrate that this variant disrupts a splicing enhancer sequence, which causes skipping of exon 5 and ultimately results in decreased protein activity (Vullamier-Barrot et al., 1999; Le Bizec et al., 2005; Smith et al., 2006).
• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 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, hyperinsulinemic hypoglycemia with polycystic kidney disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946
• PP5: Variant 16-8811146-G-A is Pathogenic according to our data. Variant chr16-8811146-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 21143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000303.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMM2	NM_000303.3	MANE Select	c.415G>A	p.Glu139Lys	missense	Exon 5 of 8	NP_000294.1	A0A0S2Z4J6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMM2	ENST00000268261.9	TSL:1 MANE Select	c.415G>A	p.Glu139Lys	missense	Exon 5 of 8	ENSP00000268261.4	O15305-1
	PMM2	ENST00000565221.5	TSL:1	n.*33G>A		non_coding_transcript_exon	Exon 3 of 6	ENSP00000457932.1	H3BV34
	PMM2	ENST00000567697.2	TSL:1	n.3583G>A		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1423654 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 704786

African (AFR) AF: 0.00 AC: 0 AN: 32636

American (AMR) AF: 0.00 AC: 0 AN: 41186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25488

East Asian (EAS) AF: 0.0000261 AC: 1 AN: 38306

South Asian (SAS) AF: 0.00 AC: 0 AN: 82098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 9.18e-7 AC: 1 AN: 1088758

Other (OTH) AF: 0.00 AC: 0 AN: 58766

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000248 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	PMM2-congenital disorder of glycosylation (7)
2	-	-	not provided (2)
1	-	-	Congenital cerebellar hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	0.015
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.70
Sift	Benign	0.11	T
Sift4G	Benign	0.24	T
Polyphen		0.069	B
Vest4		0.92
MutPred		0.86		Gain of ubiquitination at E139 (P = 0.0117)
MVP		0.91
MPC		0.019
ClinPred		0.89	D
GERP RS		5.4
Varity_R		0.79
gMVP		0.82
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs80338703; hg19: chr16-8905003;