rs431905501

Positions:

• chrX-78123234-GTC-ATG

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS1_Moderate PM2 PP3 PP5

The NM_000291.4(PGK1):​c.796_798delGTCinsATG​(p.Val266Met) variant causes a missense 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 Pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

• Frequency: Genomes: not found (cov: 23)
• Consequence: PGK1 NM_000291.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.53

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 Likely_pathogenic. Variant got 6 ACMG points.

• PS1: Transcript NM_000291.4 (PGK1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant X-78123234-GTC-ATG is Pathogenic according to our data. Variant chrX-78123234-GTC-ATG is described in ClinVar as [Pathogenic]. Clinvar id is 9944.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PGK1	NM_000291.4	c.796_798delGTCinsATG	p.Val266Met	missense_variant		ENST00000373316.5	NP_000282.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PGK1	ENST00000373316.5	c.796_798delGTCinsATG	p.Val266Met	missense_variant		1	NM_000291.4	ENSP00000362413.4
PGK1	ENST00000474281.1	n.203_205delGTCinsATG		non_coding_transcript_exon_variant	2/2	1
PGK1	ENST00000644362.1	c.712_714delGTCinsATG	p.Val238Met	missense_variant				ENSP00000496140.1

Frequencies

GnomAD3 genomes Cov.: 23

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

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1981

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs431905501; hg19: chrX-77378731;