rs431905502

Variant names:

• chrX-78118098-TGAA-T
• rs431905502
• NM_000291.4:c.574_576delAAG

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_000291.4(PGK1):​c.574_576delAAG​(p.Lys192del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 21)
• Consequence: PGK1 NM_000291.4 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 U:1
• Conservation: PhyloP100: 9.90

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
• PM4: Nonframeshift variant in NON repetitive region in NM_000291.4. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGK1	NM_000291.4	c.574_576delAAG	p.Lys192del	conservative_inframe_deletion	Exon 6 of 11	ENST00000373316.5	NP_000282.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGK1	ENST00000373316.5	c.574_576delAAG	p.Lys192del	conservative_inframe_deletion	Exon 6 of 11	1	NM_000291.4	ENSP00000362413.4
PGK1	ENST00000644362.1	c.490_492delAAG	p.Lys164del	conservative_inframe_deletion	Exon 6 of 11			ENSP00000496140.1
PGK1	ENST00000491291.1	n.566_568delAAG		non_coding_transcript_exon_variant	Exon 6 of 7	5

Frequencies

GnomAD3 genomes Cov.: 21

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 21

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Jan 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

PGK1-related disorder Uncertain:1

Aug 14, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PGK1 c.574_576delAAG variant is predicted to result in an in-frame deletion (p.Lys192del). This variant was reported in an individual with phosphoglycerate kinase deficiency (Yoshida and Davé. 1995. PubMed ID: 8673469). A missense variant at this amino acid position, described as p.Lys192Met, has been reported in a patient with cerebral palsy (Rosello et al. 2021. PubMed ID: 33177673). The c.574_576del (p.Lys192del) variant has not been reported in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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: rs431905502; hg19: chrX-77373595;