19-34365325-A-G

Variant names:

• chr19-34365325-A-G
• rs137853586
• NM_000175.5:c.59A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_000175.5(GPI):​c.59A>G​(p.His20Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000695 in 1,439,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H20P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GPI NM_000175.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.17
• Publications: 0 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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-34365325-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 13644.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.30846095).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPI	NM_000175.5	c.59A>G	p.His20Arg	missense_variant	Exon 1 of 18	ENST00000356487.11	NP_000166.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPI	ENST00000356487.11	c.59A>G	p.His20Arg	missense_variant	Exon 1 of 18	1	NM_000175.5	ENSP00000348877.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1439082 Hom.: 0 Cov.: 33 AF XY: 0.00000140 AC XY: 1 AN XY: 716354

African (AFR) AF: 0.00 AC: 0 AN: 30700

American (AMR) AF: 0.00 AC: 0 AN: 43172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25348

East Asian (EAS) AF: 0.00 AC: 0 AN: 37368

South Asian (SAS) AF: 0.00 AC: 0 AN: 84322

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1102890

Other (OTH) AF: 0.00 AC: 0 AN: 59300

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.0042	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Benign	0.64
DEOGEN2	Benign	0.036	.;.;T;.;.;.;T;T;T;T;.;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.63
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.63	T;T;.;T;T;T;.;.;.;.;T;T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.9	.;.;.;.;.;.;.;L;.;.;.;L
PhyloP100		4.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.7	.;.;.;.;N;.;.;.;.;.;.;N
REVEL	Benign	0.24
Sift	Benign	0.054	.;.;.;.;T;.;.;.;.;.;.;D
Sift4G	Benign	0.24	T;T;T;.;T;.;T;.;T;T;T;T
Polyphen		0.0010	.;.;.;.;.;.;.;B;.;.;.;B
Vest4		0.25, 0.24
MutPred		0.36		.;.;.;.;.;.;Gain of MoRF binding (P = 0.0275);Gain of MoRF binding (P = 0.0275);Gain of MoRF binding (P = 0.0275);Gain of MoRF binding (P = 0.0275);Gain of MoRF binding (P = 0.0275);Gain of MoRF binding (P = 0.0275);
MVP		0.93
MPC		0.59
ClinPred		0.27	T
GERP RS		3.8
PromoterAI		-0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.25
gMVP		0.38
Mutation Taster		=26/74	disease causing

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: rs137853586; hg19: chr19-34856230;