rs2075827

chr16-8847961-A-Cchr16-8847961-A-T

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.*136A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 668,580 control chromosomes in the GnomAD database, including 24,247 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4994 hom., cov: 33)
  • Exomes 𝑓: 0.27 (19253 hom.)
• Consequence: PMM2 NM_000303.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0670

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=-0.91).
• BP6: Variant 16-8847961-A-C is Benign according to our data. Variant chr16-8847961-A-C is described in ClinVar as [Benign]. Clinvar id is 321229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-8847961-A-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMM2	NM_000303.3	c.*136A>C		3_prime_UTR_variant	8/8	ENST00000268261.9
PMM2	XM_047434215.1	c.*136A>C		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMM2	ENST00000268261.9	c.*136A>C		3_prime_UTR_variant	8/8	1	NM_000303.3	P1
	ENST00000567942.1	n.119T>G		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38450 AN: 152032 Hom.: 4994 Cov.: 33

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.245

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.340

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.245

GnomAD4 exome AF: 0.268 AC: 138660 AN: 516430 Hom.: 19253 Cov.: 6 AF XY: 0.273 AC XY: 75198 AN XY: 275032

Gnomad4 AFR exome AF: 0.222

Gnomad4 AMR exome AF: 0.185

Gnomad4 ASJ exome AF: 0.220

Gnomad4 EAS exome AF: 0.310

Gnomad4 SAS exome AF: 0.337

Gnomad4 FIN exome AF: 0.284

Gnomad4 NFE exome AF: 0.264

Gnomad4 OTH exome AF: 0.260

GnomAD4 genome AF: 0.253 AC: 38456 AN: 152150 Hom.: 4994 Cov.: 33 AF XY: 0.256 AC XY: 19070 AN XY: 74392

Gnomad4 AFR AF: 0.220

Gnomad4 AMR AF: 0.214

Gnomad4 ASJ AF: 0.223

Gnomad4 EAS AF: 0.320

Gnomad4 SAS AF: 0.340

Gnomad4 FIN AF: 0.298

Gnomad4 NFE AF: 0.265

Gnomad4 OTH AF: 0.247

Alfa AF: 0.258 Hom.: 10314

Bravo AF: 0.240

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	-0.91
Cadd	Benign	1.4
Dann	Benign	0.53

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: rs2075827; hg19: chr16-8941818;