rs8191371

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3BP4_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I208V) has been classified as Uncertain significance.

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

Publications

16 publications found

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 Gene-Disease associations (from GenCC):

hemolytic anemia due to glucophosphate isomerase deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

GPI links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, MutationAssessor, phyloP100way_vertebrate, PrimateAI, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

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 Benign/Likely_benign. ClinVar VariationId is 402910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPI	NM_000175.5 link	c.623T>C	p.Ile208Thr	missense_variant	Exon 6 of 18	ENST00000356487.11	NP_000166.2	P06744-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPI	ENST00000356487.11 link	c.623T>C	p.Ile208Thr	missense_variant	Exon 6 of 18	1	NM_000175.5	ENSP00000348877.3		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

GnomAD2 exomes

AF:

0.0156

AC:

3931

AN:

251432

AF XY:

0.0161

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 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

African (AFR)

AF:

0.00314

AC:

105

AN:

33480

American (AMR)

AF:

0.00655

AC:

293

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0178

AC:

464

AN:

26136

East Asian (EAS)

AF:

0.000907

AC:

AN:

39700

South Asian (SAS)

AF:

0.0191

AC:

1645

AN:

86256

European-Finnish (FIN)

AF:

0.0125

AC:

667

AN:

53418

Middle Eastern (MID)

AF:

0.0186

AC:

107

AN:

5768

European-Non Finnish (NFE)

AF:

0.0240

AC:

26653

AN:

1111974

Other (OTH)

AF:

0.0167

AC:

1010

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

1743

3486

5228

6971

8714

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1002

2004

3006

4008

5010

<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:

0.0146

AC:

2224

AN:

152256

Hom.:

Cov.:

AF XY:

0.0144

AC XY:

1072

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00486

AC:

202

AN:

41544

American (AMR)

AF:

0.00883

AC:

135

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0164

AC:

AN:

3470

East Asian (EAS)

AF:

0.000773

AC:

AN:

5172

South Asian (SAS)

AF:

0.0220

AC:

106

AN:

4824

European-Finnish (FIN)

AF:

0.0117

AC:

124

AN:

10620

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0223

AC:

1518

AN:

68014

Other (OTH)

AF:

0.0156

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

108

216

323

431

539

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0197

Hom.:

134

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GPI: PP3, BS1, BS2 -

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GPI-related disorder

Benign:1

Mar 06, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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

PhyloP100

8.0

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

Mutation Taster

=38/62

polymorphism (auto)

(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