rs8191371

chr19-34377871-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 8.02

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]

ACMG classification

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 GnomAd at 2223 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPI	NM_000175.5	c.623T>C	p.Ile208Thr	missense_variant	6/18	ENST00000356487.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPI	ENST00000356487.11	c.623T>C	p.Ile208Thr	missense_variant	6/18	1	NM_000175.5	P1

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2223 AN: 152138 Hom.: 24 Cov.: 31

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.: 45 AF XY: 0.0161 AC XY: 2189 AN XY: 135904

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.: 32 AF XY: 0.0211 AC XY: 15355 AN XY: 727226

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.: 24 Cov.: 31 AF XY: 0.0144 AC XY: 1072 AN XY: 74466

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.: 66

Bravo AF: 0.0135

TwinsUK AF: 0.0232 AC: 86

ALSPAC AF: 0.0257 AC: 99

ESP6500AA AF: 0.00545 AC: 24

ESP6500EA AF: 0.0203 AC: 175

ExAC AF: 0.0155 AC: 1885

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	GPI: PP3, BS1, BS2 -

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, criteria provided, single submitter

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	T
BayesDel_noAF	Pathogenic	0.14
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;.;D
MetaRNN	Benign	0.013	T;T;T;T
MetaSVM	Uncertain	0.63	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
REVEL	Pathogenic	0.74
Polyphen		0.98	.;.;D;D
Vest4		0.41
MPC		1.4
ClinPred		0.079	T
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

Other links and lift over

dbSNP: rs8191371; hg19: chr19-34868776; COSMIC: COSV99066716; COSMIC: COSV99066716;