chr16-8848000-G-A

Variant names:

• chr16-8848000-G-A
• rs2072688
• ENST00000565221.5:n.*534G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000565221.5(PMM2):​n.*534G>A variant causes a non coding transcript exon 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 ENST00000565221.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.685
• Publications: 8 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

ENSG00000260350 (HGNC:58482):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
PMM2	NM_000303.3	c.*175G>A		3_prime_UTR_variant	Exon 8 of 8	ENST00000268261.9	NP_000294.1
PMM2	XM_047434215.1	c.*175G>A		3_prime_UTR_variant	Exon 6 of 6		XP_047290171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMM2	ENST00000268261.9	c.*175G>A		3_prime_UTR_variant	Exon 8 of 8	1	NM_000303.3	ENSP00000268261.4

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

African (AFR) AF: 0.266 AC: 3538 AN: 13318

American (AMR) AF: 0.184 AC: 4448 AN: 24180

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 3137 AN: 14510

East Asian (EAS) AF: 0.310 AC: 9518 AN: 30710

South Asian (SAS) AF: 0.333 AC: 16260 AN: 48870

European-Finnish (FIN) AF: 0.284 AC: 8289 AN: 29218

Middle Eastern (MID) AF: 0.231 AC: 468 AN: 2026

European-Non Finnish (NFE) AF: 0.264 AC: 72227 AN: 273082

Other (OTH) AF: 0.263 AC: 6948 AN: 26432

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

African (AFR) AF: 0.264 AC: 10927 AN: 41464

American (AMR) AF: 0.217 AC: 3323 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 770 AN: 3468

East Asian (EAS) AF: 0.320 AC: 1653 AN: 5172

South Asian (SAS) AF: 0.338 AC: 1627 AN: 4814

European-Finnish (FIN) AF: 0.298 AC: 3145 AN: 10566

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.265 AC: 18016 AN: 67974

Other (OTH) AF: 0.250 AC: 528 AN: 2112

Alfa AF: 0.255 Hom.: 6555

Bravo AF: 0.254

Asia WGS AF: 0.332 AC: 1155 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PMM2-congenital disorder of glycosylation Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.3
DANN	Benign	0.68
PhyloP100		-0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2072688; hg19: chr16-8941857;