Genetic Variant PGK1:p.Gly306Asp (chrX-78123355-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000291.4(PGK1):c.917G>A(p.Gly306Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000914 in 1,094,651 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G306V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

PGK1
NM_000291.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.60

Publications

0 publications found

Variant links:

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]

PGK1 Gene-Disease associations (from GenCC):

glycogen storage disease due to phosphoglycerate kinase 1 deficiency
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Genomics England PanelApp

PGK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.92

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGK1	NM_000291.4 link	c.917G>A	p.Gly306Asp	missense_variant	Exon 8 of 11	ENST00000373316.5	NP_000282.1	P00558-1V9HWF4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PGK1	ENST00000373316.5 link	c.917G>A	p.Gly306Asp	missense_variant	Exon 8 of 11	1	NM_000291.4	ENSP00000362413.4	P00558-1
PGK1	ENST00000644362.1 link	c.833G>A	p.Gly278Asp	missense_variant	Exon 8 of 11			ENSP00000496140.1	P00558-2
PGK1	ENST00000474281.1 link	n.*17G>A		downstream_gene_variant		1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.14e-7

AC:

AN:

1094651

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

360121

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26353

American (AMR)

AF:

0.00

AC:

AN:

35097

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19345

East Asian (EAS)

AF:

0.00

AC:

AN:

30181

South Asian (SAS)

AF:

0.00

AC:

AN:

53852

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40475

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4115

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

839267

Other (OTH)

AF:

0.00

AC:

AN:

45966

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

.;D

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.86

D;D

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Pathogenic

0.87

MutationAssessor

Uncertain

2.2

.;M

PhyloP100

7.6

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-6.7

.;D

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

.;D

Sift4G

Benign

0.12

.;T

Polyphen

1.0

.;D

Vest4

0.69

MutPred

0.62

.;Loss of glycosylation at S305 (P = 0.0289);

MVP

0.95

MPC

0.61

ClinPred

1.0

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.99

gMVP

0.82

Mutation Taster

=66/34

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over