rs587777405

chr1-63631759-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_002633.3(PGM1):c.661del(p.Arg221ValfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: PGM1 NM_002633.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.593

Genes affected

PGM1 (HGNC:8905): (phosphoglucomutase 1) The protein encoded by this gene is an isozyme of phosphoglucomutase (PGM) and belongs to the phosphohexose mutase family. There are several PGM isozymes, which are encoded by different genes and catalyze the transfer of phosphate between the 1 and 6 positions of glucose. In most cell types, this PGM isozyme is predominant, representing about 90% of total PGM activity. In red cells, PGM2 is a major isozyme. This gene is highly polymorphic. Mutations in this gene cause glycogen storage disease type 14. Alternativley spliced transcript variants encoding different isoforms have been identified in this gene.[provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-63631759-TC-T is Pathogenic according to our data. Variant chr1-63631759-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 133290.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGM1	NM_002633.3	c.661del	p.Arg221ValfsTer13	frameshift_variant	4/11	ENST00000371084.8
PGM1	NM_001172818.1	c.715del	p.Arg239ValfsTer13	frameshift_variant	4/11
PGM1	NM_001172819.2	c.70del	p.Arg24ValfsTer13	frameshift_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGM1	ENST00000371084.8	c.661del	p.Arg221ValfsTer13	frameshift_variant	4/11	1	NM_002633.3	P1
PGM1	ENST00000650546.1	c.661del	p.Arg221ValfsTer13	frameshift_variant	4/12
PGM1	ENST00000371083.4	c.715del	p.Arg239ValfsTer13	frameshift_variant	4/11	2
PGM1	ENST00000540265.5	c.70del	p.Arg24ValfsTer13	frameshift_variant	4/11	2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251128 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135708

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000657 AC: 96 AN: 1461562 Hom.: 0 Cov.: 30 AF XY: 0.0000550 AC XY: 40 AN XY: 727108

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000792

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74338

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000264

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

PGM1-congenital disorder of glycosylation Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 31, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 133290). This premature translational stop signal has been observed in individual(s) with PGM1 deficiency (PMID: 24499211). This variant is present in population databases (rs758688811, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Arg221Valfs*13) in the PGM1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PGM1 are known to be pathogenic (PMID: 22492991). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 06, 2014	- -

Computational scores

Source: dbNSFP v4.3

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: rs587777405; hg19: chr1-64097430;