19-34368552-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000175.5(GPI):c.283-31G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 1,611,318 control chromosomes in the GnomAD database, including 176,357 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.56 (27096 hom., cov: 32)
  • Exomes 𝑓: 0.44 (149261 hom.)
• Consequence: GPI NM_000175.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.92

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-34368552-G-A is Benign according to our data. Variant chr19-34368552-G-A is described in ClinVar as [Benign]. Clinvar id is 1281520.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.846 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPI	NM_000175.5	c.283-31G>A		intron_variant		ENST00000356487.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPI	ENST00000356487.11	c.283-31G>A		intron_variant		1	NM_000175.5	P1

Frequencies

GnomAD3 genomes AF: 0.561 AC: 85262 AN: 151854 Hom.: 27032 Cov.: 32

Gnomad AFR AF: 0.854

Gnomad AMI AF: 0.470

Gnomad AMR AF: 0.492

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.819

Gnomad SAS AF: 0.575

Gnomad FIN AF: 0.468

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.403

Gnomad OTH AF: 0.523

GnomAD3 exomes AF: 0.508 AC: 127132 AN: 250430 Hom.: 35118 AF XY: 0.497 AC XY: 67279 AN XY: 135500

Gnomad AFR exome AF: 0.860

Gnomad AMR exome AF: 0.527

Gnomad ASJ exome AF: 0.438

Gnomad EAS exome AF: 0.830

Gnomad SAS exome AF: 0.561

Gnomad FIN exome AF: 0.471

Gnomad NFE exome AF: 0.400

Gnomad OTH exome AF: 0.458

GnomAD4 exome AF: 0.439 AC: 640186 AN: 1459344 Hom.: 149261 Cov.: 36 AF XY: 0.440 AC XY: 319665 AN XY: 725940

Gnomad4 AFR exome AF: 0.869

Gnomad4 AMR exome AF: 0.523

Gnomad4 ASJ exome AF: 0.437

Gnomad4 EAS exome AF: 0.823

Gnomad4 SAS exome AF: 0.559

Gnomad4 FIN exome AF: 0.474

Gnomad4 NFE exome AF: 0.395

Gnomad4 OTH exome AF: 0.479

GnomAD4 genome AF: 0.562 AC: 85388 AN: 151974 Hom.: 27096 Cov.: 32 AF XY: 0.566 AC XY: 42079 AN XY: 74288

Gnomad4 AFR AF: 0.854

Gnomad4 AMR AF: 0.492

Gnomad4 ASJ AF: 0.433

Gnomad4 EAS AF: 0.819

Gnomad4 SAS AF: 0.576

Gnomad4 FIN AF: 0.468

Gnomad4 NFE AF: 0.403

Gnomad4 OTH AF: 0.521

Alfa AF: 0.482 Hom.: 4224

Bravo AF: 0.573

Asia WGS AF: 0.703 AC: 2445 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.029
Dann	Benign	0.60
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: rs2099099; hg19: chr19-34859457;