rs138851144

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000291.4(PGK1):c.248T>C(p.Val83Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,209,846 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000017 ( 0 hom. 3 hem. )

Consequence

PGK1
NM_000291.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.228

Publications

5 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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.030184656).

BS2

High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGK1	NM_000291.4 link	c.248T>C	p.Val83Ala	missense_variant	Exon 3 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.248T>C	p.Val83Ala	missense_variant	Exon 3 of 11	1	NM_000291.4	ENSP00000362413.4	P00558-1
PGK1	ENST00000644362.1 link	c.164T>C	p.Val55Ala	missense_variant	Exon 3 of 11			ENSP00000496140.1	P00558-2
PGK1	ENST00000491291.1 link	n.240T>C		non_coding_transcript_exon_variant	Exon 3 of 7	5
PGK1	ENST00000477335.5 link	n.*31T>C		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000447

AC:

AN:

111966

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000974

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000218

AC:

AN:

183462

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000366

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000173

AC:

AN:

1097880

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

363236

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26401

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19384

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54141

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40533

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.0000226

AC:

AN:

841790

Other (OTH)

AF:

0.00

AC:

AN:

46083

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.0000447

AC:

AN:

111966

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34120

show subpopulations

African (AFR)

AF:

0.0000974

AC:

AN:

30805

American (AMR)

AF:

0.00

AC:

AN:

10542

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3588

South Asian (SAS)

AF:

0.00

AC:

AN:

2681

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6097

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000376

AC:

AN:

53168

Other (OTH)

AF:

0.00

AC:

AN:

1513

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease due to phosphoglycerate kinase 1 deficiency

Uncertain:2

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 03, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Aug 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature in individuals affected with PGK1-related conditions. This variant is present in population databases (rs138851144, gnomAD 0.008%), including at least one homozygous and/or hemizygous individual. This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 83 of the PGK1 protein (p.Val83Ala). ClinVar contains an entry for this variant (Variation ID: 547849). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PGK1 protein function. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.54

CADD

Benign

6.5

(source)

DANN

Benign

0.49

DEOGEN2

Uncertain

0.52

.;D

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.73

T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.030

T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

-1.9

.;N

PhyloP100

0.23

PrimateAI

Benign

0.28

PROVEAN

Benign

1.3

.;N

REVEL

Benign

0.19

Sift

Benign

0.90

.;T

Sift4G

Benign

0.77

.;T

Polyphen

0.0

.;B

Vest4

0.19

MVP

0.32

MPC

0.13

ClinPred

0.019

GERP RS

-3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.092

gMVP

0.22

Mutation Taster

=92/8

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over