rs8191371

Positions:

chr19-34377871-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000175.5(GPI):c.623T>C(p.Ile208Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,614,108 control chromosomes in the GnomAD database, including 420 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 24 hom., cov: 31)

Exomes 𝑓: 0.021 ( 396 hom. )

Consequence

GPI
NM_000175.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 8.02

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01349929).

BP6

Variant 19-34377871-T-C is Benign according to our data. Variant chr19-34377871-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 402910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-34377871-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0146 (2224/152256) while in subpopulation NFE AF= 0.0223 (1518/68014). AF 95% confidence interval is 0.0214. There are 24 homozygotes in gnomad4. There are 1072 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2224 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPI	NM_000175.5 linkuse as main transcript	c.623T>C	p.Ile208Thr	missense_variant	6/18	ENST00000356487.11	NP_000166.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPI	ENST00000356487.11 linkuse as main transcript	c.623T>C	p.Ile208Thr	missense_variant	6/18	1	NM_000175.5	ENSP00000348877	P1	P06744-1

Frequencies

GnomAD3 genomes

AF:

0.0146

AC:

2223

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00488

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.00884

Gnomad ASJ

AF:

0.0164

Gnomad EAS

AF:

0.000772

Gnomad SAS

AF:

0.0213

Gnomad FIN

AF:

0.0117

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0223

Gnomad OTH

AF:

0.0158

GnomAD3 exomes

AF:

0.0156

AC:

3931

AN:

251432

Hom.:

AF XY:

0.0161

AC XY:

2189

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00363

Gnomad AMR exome

AF:

0.00665

Gnomad ASJ exome

AF:

0.0173

Gnomad EAS exome

AF:

0.000979

Gnomad SAS exome

AF:

0.0193

Gnomad FIN exome

AF:

0.0134

Gnomad NFE exome

AF:

0.0218

Gnomad OTH exome

AF:

0.0151

GnomAD4 exome

AF:

0.0212

AC:

30980

AN:

1461852

Hom.:

396

Cov.:

AF XY:

0.0211

AC XY:

15355

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00314

Gnomad4 AMR exome

AF:

0.00655

Gnomad4 ASJ exome

AF:

0.0178

Gnomad4 EAS exome

AF:

0.000907

Gnomad4 SAS exome

AF:

0.0191

Gnomad4 FIN exome

AF:

0.0125

Gnomad4 NFE exome

AF:

0.0240

Gnomad4 OTH exome

AF:

0.0167

GnomAD4 genome

AF:

0.0146

AC:

2224

AN:

152256

Hom.:

Cov.:

AF XY:

0.0144

AC XY:

1072

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00486

Gnomad4 AMR

AF:

0.00883

Gnomad4 ASJ

AF:

0.0164

Gnomad4 EAS

AF:

0.000773

Gnomad4 SAS

AF:

0.0220

Gnomad4 FIN

AF:

0.0117

Gnomad4 NFE

AF:

0.0223

Gnomad4 OTH

AF:

0.0156

Alfa

AF:

0.0203

Hom.:

Bravo

AF:

0.0135

TwinsUK

AF:

0.0232

AC:

ALSPAC

AF:

0.0257

AC:

ESP6500AA

AF:

0.00545

AC:

ESP6500EA

AF:

0.0203

AC:

175

ExAC

AF:

0.0155

AC:

1885

Asia WGS

AF:

0.00982

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	GPI: PP3, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1.5% of total chromosomes in ExAC, 2% (1358/66686) of European chromosomes -

Hemolytic anemia due to glucophosphate isomerase deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 29, 2023

- -

GPI-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 06, 2019

This variant is classified as 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

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

.;.;D;D

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;.;D

MetaRNN

Benign

0.013

T;T;T;T

MetaSVM

Uncertain

0.63

MutationAssessor

Pathogenic

4.3

.;.;H;H

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-4.2

.;.;.;D

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

.;.;.;D

Sift4G

Pathogenic

0.0

.;.;.;D

Polyphen

0.98

.;.;D;D

Vest4

0.41

MPC

1.4

ClinPred

0.079

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.93

gMVP

0.95

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