rs28936415

Variant names:

• chr16-8811153-G-A
• rs28936415
• NM_000303.3:c.422G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-8811153-G-A
• chr16-8811153-G-T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong BP4

The NM_000303.3(PMM2):​c.422G>A​(p.Arg141His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0049 in 1,570,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R141L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0050 (0 hom.)
• Consequence: PMM2 NM_000303.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:63 O:3
• Conservation: PhyloP100: 9.79
• Publications: 152 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

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000303.3
• PM2: Variant has high frequency in the NFE (0.00557) population. However there is too low homozygotes in high coverage region: (expected more than 9, got 0).
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-8811153-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3251545.
• 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: Multiple lines of computational evidence support a deleterious effect 11: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 16-8811153-G-A is Pathogenic according to our data. Variant chr16-8811153-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 7706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.020802349). . Strength limited to SUPPORTING due to the PP5.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMM2	NM_000303.3	MANE Select	c.422G>A	p.Arg141His	missense	Exon 5 of 8	NP_000294.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMM2	ENST00000268261.9	TSL:1 MANE Select	c.422G>A	p.Arg141His	missense	Exon 5 of 8	ENSP00000268261.4
	PMM2	ENST00000565221.5	TSL:1	n.*40G>A		non_coding_transcript_exon	Exon 3 of 6	ENSP00000457932.1
	PMM2	ENST00000567697.2	TSL:1	n.3590G>A		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.00366 AC: 557 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00772

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00509

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00407 AC: 785 AN: 192974 AF XY: 0.00419

Gnomad AFR exome AF: 0.000917

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00770

Gnomad EAS exome AF: 0.000133

Gnomad FIN exome AF: 0.00824

Gnomad NFE exome AF: 0.00568

Gnomad OTH exome AF: 0.00468

GnomAD4 exome AF: 0.00503 AC: 7141 AN: 1418658 Hom.: 0 Cov.: 31 AF XY: 0.00489 AC XY: 3432 AN XY: 702556

African (AFR) AF: 0.000677 AC: 22 AN: 32484

American (AMR) AF: 0.00184 AC: 75 AN: 40844

Ashkenazi Jewish (ASJ) AF: 0.00703 AC: 179 AN: 25462

East Asian (EAS) AF: 0.0000525 AC: 2 AN: 38126

South Asian (SAS) AF: 0.000867 AC: 71 AN: 81898

European-Finnish (FIN) AF: 0.00770 AC: 390 AN: 50620

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5722

European-Non Finnish (NFE) AF: 0.00569 AC: 6175 AN: 1084906

Other (OTH) AF: 0.00386 AC: 226 AN: 58596

GnomAD4 genome AF: 0.00366 AC: 557 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.00388 AC XY: 289 AN XY: 74468

African (AFR) AF: 0.000891 AC: 37 AN: 41536

American (AMR) AF: 0.00405 AC: 62 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00772 AC: 82 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00509 AC: 346 AN: 68028

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00495 Hom.: 0

Bravo AF: 0.00349

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00536 AC: 46

ExAC AF: 0.00295 AC: 346

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
42	-	-	PMM2-congenital disorder of glycosylation (45)
12	-	-	not provided (12)
1	-	-	Cerebellar ataxia (1)
1	-	-	Cerebellar ataxia;C0007789:Cerebral palsy;C0026838:Spasticity;C0235946:Cerebral atrophy;C1848207:Poor speech;C5231391:Congenital cerebellar hypoplasia (1)
1	-	-	Cerebellar ataxia;C0011849:Diabetes mellitus;C0026850:Muscular dystrophy;C5231391:Congenital cerebellar hypoplasia (1)
1	-	-	Congenital cerebellar hypoplasia (1)
1	-	-	Congenital disorder of glycosylation (1)
1	-	-	Congenital disorder of glycosylation type I (1)
1	-	-	Focal segmental glomerulosclerosis (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	PMM2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D
MetaRNN	Benign	0.021	T
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		9.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.93
Sift	Benign	0.033	D
Sift4G	Uncertain	0.040	D
Polyphen		0.99	D
Vest4		0.89
MVP		0.98
MPC		0.041
ClinPred		0.13	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.88
gMVP		0.89
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28936415; hg19: chr16-8905010; COSMIC: COSV105092582; COSMIC: COSV105092582;