rs2072688

chr16-8848000-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000303.3(PMM2):c.*175G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 614,406 control chromosomes in the GnomAD database, including 22,908 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5473 hom., cov: 32)
  • Exomes 𝑓: 0.27 (17435 hom.)
• Consequence: PMM2 NM_000303.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.685

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-8848000-G-A is Benign according to our data. Variant chr16-8848000-G-A is described in ClinVar as [Benign]. Clinvar id is 321231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.324 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMM2	NM_000303.3	c.*175G>A		3_prime_UTR_variant	8/8	ENST00000268261.9
PMM2	XM_047434215.1	c.*175G>A		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMM2	ENST00000268261.9	c.*175G>A		3_prime_UTR_variant	8/8	1	NM_000303.3	P1
	ENST00000567942.1	n.90-10C>T		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40239 AN: 151944 Hom.: 5469 Cov.: 32

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.320

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.248

GnomAD4 exome AF: 0.270 AC: 124833 AN: 462346 Hom.: 17435 Cov.: 4 AF XY: 0.274 AC XY: 67065 AN XY: 244962

Gnomad4 AFR exome AF: 0.266

Gnomad4 AMR exome AF: 0.184

Gnomad4 ASJ exome AF: 0.216

Gnomad4 EAS exome AF: 0.310

Gnomad4 SAS exome AF: 0.333

Gnomad4 FIN exome AF: 0.284

Gnomad4 NFE exome AF: 0.264

Gnomad4 OTH exome AF: 0.263

GnomAD4 genome AF: 0.265 AC: 40263 AN: 152060 Hom.: 5473 Cov.: 32 AF XY: 0.268 AC XY: 19891 AN XY: 74340

Gnomad4 AFR AF: 0.264

Gnomad4 AMR AF: 0.217

Gnomad4 ASJ AF: 0.222

Gnomad4 EAS AF: 0.320

Gnomad4 SAS AF: 0.338

Gnomad4 FIN AF: 0.298

Gnomad4 NFE AF: 0.265

Gnomad4 OTH AF: 0.250

Alfa AF: 0.256 Hom.: 5030

Bravo AF: 0.254

Asia WGS AF: 0.332 AC: 1155 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PMM2-congenital disorder of glycosylation Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	2.3
Dann	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2072688; hg19: chr16-8941857;