chr19-34399417-G-A

Variant names:

• chr19-34399417-G-A
• rs2301263
• NM_000175.5:c.1398+82G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000175.5(GPI):​c.1398+82G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.788 in 1,592,794 control chromosomes in the GnomAD database, including 505,099 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (37688 hom., cov: 32)
  • Exomes 𝑓: 0.80 (467411 hom.)
• Consequence: GPI NM_000175.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.12
• Publications: 6 publications found

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]

GPI Gene-Disease associations (from GenCC):

• hemolytic anemia due to glucophosphate isomerase deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000266953 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-34399417-G-A is Benign according to our data. Variant chr19-34399417-G-A is described in ClinVar as Benign. ClinVar VariationId is 1237555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.822 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPI	NM_000175.5	c.1398+82G>A		intron_variant	Intron 15 of 17	ENST00000356487.11	NP_000166.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPI	ENST00000356487.11	c.1398+82G>A		intron_variant	Intron 15 of 17	1	NM_000175.5	ENSP00000348877.3
ENSG00000266953	ENST00000592740.5	c.192+2760G>A		intron_variant	Intron 2 of 4	3		ENSP00000468690.1

Frequencies

GnomAD3 genomes AF: 0.672 AC: 102142 AN: 151990 Hom.: 37692 Cov.: 32

Gnomad AFR AF: 0.347

Gnomad AMI AF: 0.746

Gnomad AMR AF: 0.702

Gnomad ASJ AF: 0.789

Gnomad EAS AF: 0.800

Gnomad SAS AF: 0.638

Gnomad FIN AF: 0.797

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.828

Gnomad OTH AF: 0.706

GnomAD4 exome AF: 0.800 AC: 1152682 AN: 1440686 Hom.: 467411 Cov.: 27 AF XY: 0.798 AC XY: 572591 AN XY: 717974

African (AFR) AF: 0.332 AC: 10931 AN: 32954

American (AMR) AF: 0.697 AC: 31101 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.775 AC: 20142 AN: 26002

East Asian (EAS) AF: 0.833 AC: 32990 AN: 39602

South Asian (SAS) AF: 0.642 AC: 54684 AN: 85224

European-Finnish (FIN) AF: 0.794 AC: 42263 AN: 53254

Middle Eastern (MID) AF: 0.694 AC: 3969 AN: 5716

European-Non Finnish (NFE) AF: 0.833 AC: 910570 AN: 1093502

Other (OTH) AF: 0.770 AC: 46032 AN: 59786

GnomAD4 genome AF: 0.672 AC: 102150 AN: 152108 Hom.: 37688 Cov.: 32 AF XY: 0.669 AC XY: 49758 AN XY: 74364

African (AFR) AF: 0.347 AC: 14371 AN: 41474

American (AMR) AF: 0.702 AC: 10728 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.789 AC: 2733 AN: 3466

East Asian (EAS) AF: 0.800 AC: 4130 AN: 5160

South Asian (SAS) AF: 0.637 AC: 3074 AN: 4826

European-Finnish (FIN) AF: 0.797 AC: 8429 AN: 10582

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.828 AC: 56301 AN: 68000

Other (OTH) AF: 0.706 AC: 1489 AN: 2108

Alfa AF: 0.711 Hom.: 6233

Bravo AF: 0.656

Asia WGS AF: 0.680 AC: 2364 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.062
DANN	Benign	0.61
PhyloP100		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2301263; hg19: chr19-34890322; COSMIC: COSV55825888; COSMIC: COSV55825888;