19-34365408-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000175.5(GPI):c.122+20G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00373 in 1,560,270 control chromosomes in the GnomAD database, including 186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (108 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (78 hom.)
• Consequence: GPI NM_000175.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.13

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 (BayesDel_noAF=-0.78).
• BP6: Variant 19-34365408-G-A is Benign according to our data. Variant chr19-34365408-G-A is described in ClinVar as [Benign]. Clinvar id is 811678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.065 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPI	NM_000175.5	c.122+20G>A		intron_variant		ENST00000356487.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPI	ENST00000356487.11	c.122+20G>A		intron_variant		1	NM_000175.5	P1

Frequencies

GnomAD3 genomes AF: 0.0193 AC: 2928 AN: 152090 Hom.: 105 Cov.: 32

Gnomad AFR AF: 0.0668

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.00480 AC: 928 AN: 193474 Hom.: 29 AF XY: 0.00354 AC XY: 385 AN XY: 108616

Gnomad AFR exome AF: 0.0820

Gnomad AMR exome AF: 0.00367

Gnomad ASJ exome AF: 0.00722

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000379

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000468

Gnomad OTH exome AF: 0.00275

GnomAD4 exome AF: 0.00205 AC: 2881 AN: 1408072 Hom.: 78 Cov.: 33 AF XY: 0.00183 AC XY: 1285 AN XY: 700362

Gnomad4 AFR exome AF: 0.0705

Gnomad4 AMR exome AF: 0.00401

Gnomad4 ASJ exome AF: 0.00612

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000852

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000168

Gnomad4 OTH exome AF: 0.00511

GnomAD4 genome AF: 0.0193 AC: 2944 AN: 152198 Hom.: 108 Cov.: 32 AF XY: 0.0186 AC XY: 1387 AN XY: 74422

Gnomad4 AFR AF: 0.0670

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.0171

Alfa AF: 0.00144 Hom.: 0

Bravo AF: 0.0207

Asia WGS AF: 0.00521 AC: 19 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hemolytic anemia due to glucophosphate isomerase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 13, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	5.0
Dann	Benign	0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs8191360; hg19: chr19-34856313;