19-34364916-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.349

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 -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 GnomAd at 190 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPI	NM_001289789.1	c.7G>A	p.Ala3Thr	missense_variant	1/19
GPI	NM_001184722.1	c.7G>A	p.Ala3Thr	missense_variant	1/18
GPI	XM_011526754.4	c.7G>A	p.Ala3Thr	missense_variant	2/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPI	ENST00000415930.8	c.7G>A	p.Ala3Thr	missense_variant	1/19	2
GPI	ENST00000588991.7	c.7G>A	p.Ala3Thr	missense_variant	1/18	2
GPI	ENST00000592277.5	c.7G>A	p.Ala3Thr	missense_variant	2/6	4

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 190 AN: 152226 Hom.: 1 Cov.: 32

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: 21 AN: 122978 Hom.: 0 AF XY: 0.000119 AC XY: 8 AN XY: 67252

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.: 0 Cov.: 21 AF XY: 0.0000907 AC XY: 59 AN XY: 650686

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.: 1 Cov.: 32 AF XY: 0.00107 AC XY: 80 AN XY: 74488

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.: 0

Bravo AF: 0.00134

ExAC AF: 0.000409 AC: 7

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

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	4.7
Dann	Uncertain	0.99
Eigen	Benign	-0.73
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.48	T;T;.;T;T;T
MetaRNN	Benign	0.0063	T;T;T;T;T;T
MetaSVM	Uncertain	-0.033	T
MutationTaster	Benign	1.0	N
Sift4G	Pathogenic	0.0	D;D;D;.;T;.
Vest4		0.28
MVP		0.88
MPC		0.80
ClinPred		0.14	T
GERP RS		-1.1
gMVP		0.19

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs549433538; hg19: chr19-34855821;