rs137852530

Positions:

• chrX-78124992-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000291.4(PGK1):​c.1055C>A​(p.Thr352Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,216 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as other (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: PGK1 NM_000291.4 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 7.38

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PGK1	NM_000291.4	c.1055C>A	p.Thr352Asn	missense_variant	9/11	ENST00000373316.5	NP_000282.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PGK1	ENST00000373316.5	c.1055C>A	p.Thr352Asn	missense_variant	9/11	1	NM_000291.4	ENSP00000362413	P1
PGK1	ENST00000644362.1	c.971C>A	p.Thr324Asn	missense_variant	9/11			ENSP00000496140
PGK1	ENST00000476531.1	n.49C>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097216 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 362588

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Phosphoglycerate kinase electrophoretic variant PGK II Other:1

other, no assertion criteria provided

literature only

OMIM

Apr 12, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	.;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.5	.;H
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-4.0	.;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	.;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		1.0	.;D
Vest4		0.93
MutPred		0.33		.;Loss of phosphorylation at T352 (P = 0.1602);
MVP		0.93
MPC		0.50
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.9
Varity_R		0.99
gMVP		0.99

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: rs137852530; hg19: chrX-77380489; COSMIC: COSV105203509; COSMIC: COSV105203509;