rs137852538

Variant names:

• chrX-78117385-A-T
• rs137852538
• NM_000291.4:c.491A>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000291.4(PGK1):​c.491A>T​(p.Asp164Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PGK1 NM_000291.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.31

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant X-78117385-A-T is Pathogenic according to our data. Variant chrX-78117385-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 9954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGK1	NM_000291.4	c.491A>T	p.Asp164Val	missense_variant	Exon 5 of 11	ENST00000373316.5	NP_000282.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGK1	ENST00000373316.5	c.491A>T	p.Asp164Val	missense_variant	Exon 5 of 11	1	NM_000291.4	ENSP00000362413.4
PGK1	ENST00000644362.1	c.407A>T	p.Asp136Val	missense_variant	Exon 5 of 11			ENSP00000496140.1
PGK1	ENST00000491291.1	n.483A>T		non_coding_transcript_exon_variant	Exon 5 of 7	5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Aug 29, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect in enzyme activity (PMID: 22348148); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16740138, 7577653, 24970202, 26975778, 26396085, 8043870, 30887539, 30975619, 22348148) -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glycogen storage disease due to phosphoglycerate kinase 1 deficiency Pathogenic:1

Jul 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.80
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	.;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	5.3	.;H
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-8.8	.;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		1.0	.;D
Vest4		0.99
MutPred		0.97		.;Gain of MoRF binding (P = 0.0497);
MVP		1.0
MPC		0.64
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.99
gMVP		0.96

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: rs137852538; hg19: chrX-77372882;