rs782165735

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_000291.4(PGK1):c.1234G>A(p.Asp412Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000094 in 1,201,765 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 37 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D412D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000097 ( 0 hom. 36 hem. )

Consequence

PGK1
NM_000291.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 7.18

Publications

3 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.36939877).

BP6

Variant X-78125810-G-A is Benign according to our data. Variant chrX-78125810-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 493535.

BS2

High Hemizygotes in GnomAdExome4 at 36 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000291.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGK1	NM_000291.4	MANE Select	c.1234G>A	p.Asp412Asn	missense	Exon 11 of 11	NP_000282.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PGK1	ENST00000373316.5	TSL:1 MANE Select	c.1234G>A	p.Asp412Asn	missense	Exon 11 of 11	ENSP00000362413.4
PGK1	ENST00000644362.1		c.1150G>A	p.Asp384Asn	missense	Exon 11 of 11	ENSP00000496140.1
PGK1	ENST00000476531.1	TSL:2	n.503G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.0000626

AC:

AN:

111908

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000437

AC:

AN:

183263

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000979

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000973

AC:

106

AN:

1089857

Hom.:

Cov.:

AF XY:

0.000101

AC XY:

AN XY:

355709

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26267

American (AMR)

AF:

0.00

AC:

AN:

35190

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19334

East Asian (EAS)

AF:

0.00

AC:

AN:

30182

South Asian (SAS)

AF:

0.0000556

AC:

AN:

53943

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40522

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

4093

European-Non Finnish (NFE)

AF:

0.000104

AC:

AN:

834481

Other (OTH)

AF:

0.000240

AC:

AN:

45845

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

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:

0.0000626

AC:

AN:

111908

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34072

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30745

American (AMR)

AF:

0.00

AC:

AN:

10556

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2642

East Asian (EAS)

AF:

0.00

AC:

AN:

3584

South Asian (SAS)

AF:

0.00

AC:

AN:

2695

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6081

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

53174

Other (OTH)

AF:

0.00

AC:

AN:

1511

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Glycogen storage disease due to phosphoglycerate kinase 1 deficiency

Uncertain:2

Aug 29, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PGK1: BS2

Oct 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.040

MetaRNN

Benign

0.37

MetaSVM

Uncertain

0.27

MutationAssessor

Benign

1.4

PhyloP100

7.2

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.34

Sift

Benign

0.18

Sift4G

Benign

0.087

Polyphen

0.0010

Vest4

0.11

MVP

0.84

MPC

0.11

ClinPred

0.21

GERP RS

5.2

Varity_R

0.67

gMVP

0.75

Mutation Taster

=83/17

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over