rs62031146

chr16-8806384-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000303.3(PMM2):c.324G>A(p.Ala108=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,612,270 control chromosomes in the GnomAD database, including 325 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A108A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (33 hom., cov: 33)
  • Exomes 𝑓: 0.017 (292 hom.)
• Consequence: PMM2 NM_000303.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -4.39

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 16-8806384-G-A is Benign according to our data. Variant chr16-8806384-G-A is described in ClinVar as [Benign]. Clinvar id is 129976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-8806384-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0133 (2030/152282) while in subpopulation SAS AF= 0.0354 (171/4830). AF 95% confidence interval is 0.0311. There are 33 homozygotes in gnomad4. There are 984 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMM2	NM_000303.3	c.324G>A	p.Ala108=	synonymous_variant	4/8	ENST00000268261.9
PMM2	XM_047434215.1	c.75G>A	p.Ala25=	synonymous_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMM2	ENST00000268261.9	c.324G>A	p.Ala108=	synonymous_variant	4/8	1	NM_000303.3	P1

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2029 AN: 152164 Hom.: 33 Cov.: 33

Gnomad AFR AF: 0.00531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0172

Gnomad ASJ AF: 0.0521

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0352

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0163

Gnomad OTH AF: 0.0186

GnomAD3 exomes AF: 0.0167 AC: 4190 AN: 251448 Hom.: 66 AF XY: 0.0180 AC XY: 2449 AN XY: 135894

Gnomad AFR exome AF: 0.00523

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.0481

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0345

Gnomad FIN exome AF: 0.00522

Gnomad NFE exome AF: 0.0175

Gnomad OTH exome AF: 0.0181

GnomAD4 exome AF: 0.0166 AC: 24178 AN: 1459988 Hom.: 292 Cov.: 29 AF XY: 0.0173 AC XY: 12534 AN XY: 726512

Gnomad4 AFR exome AF: 0.00586

Gnomad4 AMR exome AF: 0.0119

Gnomad4 ASJ exome AF: 0.0506

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0337

Gnomad4 FIN exome AF: 0.00552

Gnomad4 NFE exome AF: 0.0160

Gnomad4 OTH exome AF: 0.0175

GnomAD4 genome AF: 0.0133 AC: 2030 AN: 152282 Hom.: 33 Cov.: 33 AF XY: 0.0132 AC XY: 984 AN XY: 74462

Gnomad4 AFR AF: 0.00534

Gnomad4 AMR AF: 0.0171

Gnomad4 ASJ AF: 0.0521

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0354

Gnomad4 FIN AF: 0.00396

Gnomad4 NFE AF: 0.0163

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.0159 Hom.: 16

Bravo AF: 0.0128

Asia WGS AF: 0.0120 AC: 46 AN: 3478

EpiCase AF: 0.0169

EpiControl AF: 0.0183

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 25, 2017	Variant summary: The PMM2 c.324G>A (p.Ala108Ala) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE site of SRp55. However, these predictions have yet to be confirmed by functional studies. This variant was found in 2137/121286 control chromosomes at a frequency of 0.0176195, which is approximately 3 times the estimated maximal expected allele frequency of a pathogenic PMM2 variant (0.0055902), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jun 17, 2015	- -

PMM2-congenital disorder of glycosylation Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 21, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	2.5
Dann	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.22		Position offset: 23

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

Publications

LitVar

Other links and lift over

dbSNP: rs62031146; hg19: chr16-8900241;