rs1801015

chr19-34377737-A-Gchr19-34377737-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000175.5(GPI):c.489A>G(p.Gly163=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0866 in 1,613,160 control chromosomes in the GnomAD database, including 9,609 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G163G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.15 (2932 hom., cov: 30)
  • Exomes 𝑓: 0.080 (6677 hom.)
• Consequence: GPI NM_000175.5 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.807

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 19-34377737-A-G is Benign according to our data. Variant chr19-34377737-A-G is described in ClinVar as [Benign]. Clinvar id is 255472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-34377737-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.807 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.337 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPI	NM_000175.5	c.489A>G	p.Gly163=	splice_region_variant, synonymous_variant	6/18	ENST00000356487.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPI	ENST00000356487.11	c.489A>G	p.Gly163=	splice_region_variant, synonymous_variant	6/18	1	NM_000175.5	P1

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23285 AN: 151678 Hom.: 2910 Cov.: 30

Gnomad AFR AF: 0.341

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.0927

Gnomad EAS AF: 0.198

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.0859

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0622

Gnomad OTH AF: 0.118

GnomAD3 exomes AF: 0.108 AC: 27032 AN: 251446 Hom.: 2217 AF XY: 0.103 AC XY: 13978 AN XY: 135908

Gnomad AFR exome AF: 0.341

Gnomad AMR exome AF: 0.0835

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.202

Gnomad SAS exome AF: 0.144

Gnomad FIN exome AF: 0.0821

Gnomad NFE exome AF: 0.0627

Gnomad OTH exome AF: 0.0893

GnomAD4 exome AF: 0.0796 AC: 116352 AN: 1461364 Hom.: 6677 Cov.: 31 AF XY: 0.0803 AC XY: 58343 AN XY: 727010

Gnomad4 AFR exome AF: 0.350

Gnomad4 AMR exome AF: 0.0846

Gnomad4 ASJ exome AF: 0.0992

Gnomad4 EAS exome AF: 0.166

Gnomad4 SAS exome AF: 0.142

Gnomad4 FIN exome AF: 0.0881

Gnomad4 NFE exome AF: 0.0610

Gnomad4 OTH exome AF: 0.105

GnomAD4 genome AF: 0.154 AC: 23349 AN: 151796 Hom.: 2932 Cov.: 30 AF XY: 0.155 AC XY: 11532 AN XY: 74228

Gnomad4 AFR AF: 0.342

Gnomad4 AMR AF: 0.105

Gnomad4 ASJ AF: 0.0927

Gnomad4 EAS AF: 0.197

Gnomad4 SAS AF: 0.156

Gnomad4 FIN AF: 0.0859

Gnomad4 NFE AF: 0.0622

Gnomad4 OTH AF: 0.120

Alfa AF: 0.0900 Hom.: 749

Bravo AF: 0.160

Asia WGS AF: 0.227 AC: 791 AN: 3478

EpiCase AF: 0.0646

EpiControl AF: 0.0656

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hemolytic anemia due to glucophosphate isomerase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 04, 2022	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	7.0
Dann	Benign	0.61
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7

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: rs1801015; hg19: chr19-34868642; COSMIC: COSV62894048; COSMIC: COSV62894048;