Variant rs137853586 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_000175.5(GPI):c.59A>C(p.His20Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000278 in 1,439,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

GPI
NM_000175.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.17

Variant links:

Genes affected

GPI (HGNC:4458): (glucose-6-phosphate isomerase) This gene encodes a member of the glucose phosphate isomerase protein family. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. In the cytoplasm, the gene product functions as a glycolytic enzyme (glucose-6-phosphate isomerase) that interconverts glucose-6-phosphate and fructose-6-phosphate. Extracellularly, the encoded protein (also referred to as neuroleukin) functions as a neurotrophic factor that promotes survival of skeletal motor neurons and sensory neurons, and as a lymphokine that induces immunoglobulin secretion. The encoded protein is also referred to as autocrine motility factor based on an additional function as a tumor-secreted cytokine and angiogenic factor. Defects in this gene are the cause of nonspherocytic hemolytic anemia and a severe enzyme deficiency can be associated with hydrops fetalis, immediate neonatal death and neurological impairment. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]

GPI links:

GPI (HGNC:):

GPI links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.964

PP5

Variant 19-34365325-A-C is Pathogenic according to our data. Variant chr19-34365325-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 13644.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPI	NM_000175.5 linkuse as main transcript	c.59A>C	p.His20Pro	missense_variant	1/18	ENST00000356487.11	NP_000166.2	P06744-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPI	ENST00000356487.11 linkuse as main transcript	c.59A>C	p.His20Pro	missense_variant	1/18	1	NM_000175.5	ENSP00000348877.3		P06744-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000131

AC:

AN:

228814

Hom.:

AF XY:

0.0000159

AC XY:

AN XY:

125622

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000286

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000278

AC:

AN:

1439082

Hom.:

Cov.:

AF XY:

0.00000419

AC XY:

AN XY:

716354

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000363

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Hemolytic anemia due to glucophosphate isomerase deficiency

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

DANN

Benign

0.48

DEOGEN2

Benign

0.098

.;.;T;.;.;.;T;D;T;T;.;D

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.57

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.78

T;T;.;T;T;T;.;.;.;.;T;T

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.96

D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.30

MutationAssessor

Uncertain

2.3

.;.;.;.;.;.;.;M;.;.;.;M

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.9

.;.;.;.;D;.;.;.;.;.;.;D

REVEL

Uncertain

0.55

Sift

Uncertain

0.028

.;.;.;.;D;.;.;.;.;.;.;D

Sift4G

Benign

0.066

T;T;T;.;T;.;T;.;T;T;T;T

Polyphen

0.0

.;.;.;.;.;.;.;B;.;.;.;B

Vest4

0.69, 0.68

MutPred

0.82

.;.;.;.;.;.;Gain of glycosylation at H20 (P = 0.0199);Gain of glycosylation at H20 (P = 0.0199);Gain of glycosylation at H20 (P = 0.0199);Gain of glycosylation at H20 (P = 0.0199);Gain of glycosylation at H20 (P = 0.0199);Gain of glycosylation at H20 (P = 0.0199);

MVP

0.93

MPC

0.96

ClinPred

0.14

GERP RS

3.8

Varity_R

0.83

gMVP

0.76

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over