Variant 19-34365258-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_000175.5(GPI):c.-9A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000569 in 1,564,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

GPI
NM_000175.5 5_prime_UTR_premature_start_codon_gain

Scores

Splicing: ADA: 0.9999

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.356

Variant links:

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 links:

GPI (HGNC:):

GPI links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000581 (82/1412318) while in subpopulation SAS AF= 0.000797 (65/81588). AF 95% confidence interval is 0.000641. There are 0 homozygotes in gnomad4_exome. There are 56 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPI	NM_000175.5 linkuse as main transcript	c.-9A>G		5_prime_UTR_premature_start_codon_gain_variant	1/18	ENST00000356487.11	NP_000166.2	P06744-1
GPI	NM_000175.5 linkuse as main transcript	c.-9A>G		5_prime_UTR_variant	1/18	ENST00000356487.11	NP_000166.2	P06744-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPI	ENST00000356487 linkuse as main transcript	c.-9A>G		5_prime_UTR_premature_start_codon_gain_variant	1/18	1	NM_000175.5	ENSP00000348877.3		P06744-1
GPI	ENST00000356487 linkuse as main transcript	c.-9A>G		5_prime_UTR_variant	1/18	1	NM_000175.5	ENSP00000348877.3		P06744-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

151956

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000109

AC:

AN:

210614

Hom.:

AF XY:

0.000172

AC XY:

AN XY:

116554

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000147

Gnomad SAS exome

AF:

0.000742

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000102

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000581

AC:

AN:

1412318

Hom.:

Cov.:

AF XY:

0.0000796

AC XY:

AN XY:

703282

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000571

Gnomad4 SAS exome

AF:

0.000797

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000917

Gnomad4 OTH exome

AF:

0.0000690

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152064

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000589

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000489

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000826

AC:

Asia WGS

AF:

0.000291

AC:

AN:

3448

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

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

Apr 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.77

CADD

Benign

DANN

Benign

0.59

Eigen

Benign

0.019

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.018

GERP RS

-1.4

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over