19-34365357-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000175.5(GPI):c.91G>C(p.Asp31His) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,438,382 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GPI NM_000175.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.55

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPI	NM_000175.5	c.91G>C	p.Asp31His	missense_variant	1/18	ENST00000356487.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPI	ENST00000356487.11	c.91G>C	p.Asp31His	missense_variant	1/18	1	NM_000175.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000435 AC: 1 AN: 229638 Hom.: 0 AF XY: 0.00000794 AC XY: 1 AN XY: 125898

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: 0.00

Gnomad OTH exome AF: 0.000179

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1438382 Hom.: 0 Cov.: 33 AF XY: 0.00000140 AC XY: 1 AN XY: 716064

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: 9.07e-7

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hemolytic anemia due to glucophosphate isomerase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Mar 14, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	22
Dann	Benign	0.95
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D;.;D;D;D;.;.;.;.;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Uncertain	0.42	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationTaster	Benign	0.55	D;D;D
PrimateAI	Uncertain	0.50	T
Sift4G	Uncertain	0.015	D;D;T;.;T;.;T;.;T;T;T;D
Polyphen		0.059	.;.;.;.;.;.;.;B;.;.;.;B
Vest4		0.33, 0.25
MutPred		0.26		.;.;.;.;.;.;Gain of MoRF binding (P = 0.0412);Gain of MoRF binding (P = 0.0412);Gain of MoRF binding (P = 0.0412);Gain of MoRF binding (P = 0.0412);Gain of MoRF binding (P = 0.0412);Gain of MoRF binding (P = 0.0412);
MVP		0.93
MPC		0.91
ClinPred		0.42	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.46

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: rs1349915053; hg19: chr19-34856262;