19-34364916-G-A

Position:

chr19-34364916-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001289789.1(GPI):c.7G>A(p.Ala3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,469,542 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

GPI
NM_001289789.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 0.349

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006276846).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00125 (190/152344) while in subpopulation AFR AF= 0.0045 (187/41592). AF 95% confidence interval is 0.00397. There are 1 homozygotes in gnomad4. There are 80 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 190 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein	UniProt
GPI	NM_001289789.1 linkuse as main transcript	c.7G>A	p.Ala3Thr	missense_variant	1/19	NP_001276718.1	A0A2U3TZU2
GPI	NM_001184722.1 linkuse as main transcript	c.7G>A	p.Ala3Thr	missense_variant	1/18	NP_001171651.1	P06744-2
GPI	XM_011526754.4 linkuse as main transcript	c.7G>A	p.Ala3Thr	missense_variant	2/20	XP_011525056.1	A0A2U3TZU2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	UniProt
GPI	ENST00000415930.8 linkuse as main transcript	c.7G>A	p.Ala3Thr	missense_variant	1/19	2	ENSP00000405573.3	A0A2U3TZU2
GPI	ENST00000588991.7 linkuse as main transcript	c.7G>A	p.Ala3Thr	missense_variant	1/18	2	ENSP00000465858.3	P06744-2
GPI	ENST00000592277.5 linkuse as main transcript	c.7G>A	p.Ala3Thr	missense_variant	2/6	4	ENSP00000466191.1	K7ELR7

Frequencies

GnomAD3 genomes

AF:

0.00125

AC:

190

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00451

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000171

AC:

AN:

122978

Hom.:

AF XY:

0.000119

AC XY:

AN XY:

67252

show subpopulations

Gnomad AFR exome

AF:

0.00359

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:

0.0000206

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000120

AC:

158

AN:

1317198

Hom.:

Cov.:

AF XY:

0.0000907

AC XY:

AN XY:

650686

show subpopulations

Gnomad4 AFR exome

AF:

0.00472

Gnomad4 AMR exome

AF:

0.0000295

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:

9.76e-7

Gnomad4 OTH exome

AF:

0.000272

GnomAD4 genome

AF:

0.00125

AC:

190

AN:

152344

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00450

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000564

Hom.:

Bravo

AF:

0.00134

ExAC

AF:

0.000409

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hemolytic anemia due to glucophosphate isomerase deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 25, 2022

- -

GPI-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.26

CADD

Benign

4.7

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0092

.;.;T;.;.;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.063

LIST_S2

Benign

0.48

T;T;.;T;T;T

MetaRNN

Benign

0.0063

T;T;T;T;T;T

MetaSVM

Uncertain

-0.033

PROVEAN

Benign

0.0

.;.;.;.;N;.

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

.;.;.;.;D;.

Sift4G

Pathogenic

0.0

D;D;D;.;T;.

Vest4

0.28

MVP

0.88

MPC

0.80

ClinPred

0.14

GERP RS

-1.1

gMVP

0.19

Splicing

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