rs797044505

Variant names:

• chrX-78118168-C-T
• rs797044505
• NM_000291.4:c.639C>T
• PGK1 p.Gly213Gly

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3 PM2 PP3 PP5

The NM_000291.4(PGK1):​c.639C>T​(p.Gly213Gly) variant causes a splice region, synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV004300120: Studies have shown that this variant is associated with altered splicing resulting in reduced mRNA expression (PMID:17661373)." and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 22)
• Consequence: PGK1 NM_000291.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.2133
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 3.74
• Publications: 3 publications found

Genes affected

PGK1 (HGNC:8896): (phosphoglycerate kinase 1) The protein encoded by this gene is a glycolytic enzyme that catalyzes the conversion of 1,3-diphosphoglycerate to 3-phosphoglycerate. The encoded protein may also act as a cofactor for polymerase alpha. Additionally, this protein is secreted by tumor cells where it participates in angiogenesis by functioning to reduce disulfide bonds in the serine protease, plasmin, which consequently leads to the release of the tumor blood vessel inhibitor angiostatin. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. Deficiency of the enzyme is associated with a wide range of clinical phenotypes hemolytic anemia and neurological impairment. Pseudogenes of this gene have been defined on chromosomes 19, 21 and the X chromosome. [provided by RefSeq, Jan 2014]

PGK1 Gene-Disease associations (from GenCC):

• glycogen storage disease due to phosphoglycerate kinase 1 deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004300120: Studies have shown that this variant is associated with altered splicing resulting in reduced mRNA expression (PMID: 17661373).; SCV005398368: Quantitative PCR on blood samples from individuals heterozygous or hemizygous for this variant has shown that it results in a reduction of PGK1 mRNA expression (PMID: 17661373).
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_ADA.
• PP5: Variant X-78118168-C-T is Pathogenic according to our data. Variant chrX-78118168-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167466.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000291.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGK1	NM_000291.4	MANE Select	c.639C>T	p.Gly213Gly	splice_region synonymous	Exon 6 of 11	NP_000282.1	P00558-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGK1	ENST00000373316.5	TSL:1 MANE Select	c.639C>T	p.Gly213Gly	splice_region synonymous	Exon 6 of 11	ENSP00000362413.4	P00558-1
	PGK1	ENST00000878879.1		c.639C>T	p.Gly213Gly	splice_region synonymous	Exon 6 of 11	ENSP00000548938.1
	PGK1	ENST00000925024.1		c.669C>T	p.Gly223Gly	splice_region synonymous	Exon 6 of 11	ENSP00000595083.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	not provided (3)
1	-	-	Glycogen storage disease due to phosphoglycerate kinase 1 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	24
DANN	Benign	0.56
PhyloP100		3.7
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Mutation Taster		=87/13	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.21
dbscSNV1_RF	Pathogenic	0.79
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.99		Position offset: -2
DS_DL_spliceai		0.49		Position offset: 2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs797044505;

hg19: chrX-77373665;

COSMIC: COSV64832752;

COSMIC: COSV64832752;