X-78118168-C-T

Position:

• chrX-78118168-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000291.4(PGK1):​c.639C>T​(p.Gly213=) 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 Likely pathogenic (★★).

• 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:2 U:1
• Conservation: PhyloP100: 3.74

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius 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 [Likely_pathogenic]. Clinvar id is 167466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PGK1	NM_000291.4	c.639C>T	p.Gly213=	splice_region_variant, synonymous_variant	6/11	ENST00000373316.5	NP_000282.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PGK1	ENST00000373316.5	c.639C>T	p.Gly213=	splice_region_variant, synonymous_variant	6/11	1	NM_000291.4	ENSP00000362413	P1
PGK1	ENST00000644362.1	c.555C>T	p.Gly185=	splice_region_variant, synonymous_variant	6/11			ENSP00000496140
PGK1	ENST00000491291.1	n.631C>T		splice_region_variant, non_coding_transcript_exon_variant	6/7	5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 04, 2023	This sequence change affects codon 213 of the PGK1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PGK1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with phosphoglycerate kinase 1 deficiency (PMID: 30111548). ClinVar contains an entry for this variant (Variation ID: 167466). Studies have shown that this variant is associated with altered splicing resulting in reduced mRNA expression (PMID: 17661373). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2018	The c.639C>T variant in the PGK1 gene has been reported previously in two brothers with phosphoglycerate kinase deficiency. They presented with muscle pain, cramps, and stiffness following heavy exercise. Their sister, who was heterozygous for the c.639C>T mutation, also experienced mild muscle stiffness during exercise (Svaasand et al., 2007). This splicing variant, which also results in a synonymous change (p.Gly213Gly), is predicted to destroy the canonical splice donor site in intron 6. The c.639C>T variant is predicted to induce a large splicing change (Xiong et al., 2014). The c.639C>T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.639C>T variant is a strong candidate for a disease-causing variant, however, the possibility it may be a rare benign variant cannot be excluded. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 20, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	24
DANN	Benign	0.56
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs797044505; hg19: chrX-77373665; COSMIC: COSV64832752; COSMIC: COSV64832752;