19-34365386-C-A

Position:

• chr19-34365386-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000175.5(GPI):​c.120C>A​(p.Phe40Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000701 in 1,427,060 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: GPI NM_000175.5 missense, splice_region
• Scores: Splicing: ADA: 0.04983
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.05

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPI	NM_000175.5	c.120C>A	p.Phe40Leu	missense_variant, splice_region_variant	1/18	ENST00000356487.11	NP_000166.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPI	ENST00000356487.11	c.120C>A	p.Phe40Leu	missense_variant, splice_region_variant	1/18	1	NM_000175.5	ENSP00000348877.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000701 AC: 10 AN: 1427060 Hom.: 0 Cov.: 33 AF XY: 0.00000563 AC XY: 4 AN XY: 710400

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000728

Gnomad4 OTH exome AF: 0.0000341

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	.;.;T;.;.;.;T;D;T;T;.;D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	D;D;.;D;D;D;.;.;.;.;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.9	.;.;.;.;.;.;.;L;.;.;.;L
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.5	.;.;.;.;D;.;.;.;.;.;.;D
REVEL	Uncertain	0.51
Sift	Benign	0.051	.;.;.;.;T;.;.;.;.;.;.;T
Sift4G	Benign	0.089	T;D;T;.;D;.;D;.;D;D;D;D
Polyphen		0.041	.;.;.;.;.;.;.;B;.;.;.;B
Vest4		0.30, 0.33
MutPred		0.65		.;.;.;.;.;.;Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.98
MPC		0.52
ClinPred		0.67	D
GERP RS		3.5
Varity_R		0.73
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.050
dbscSNV1_RF	Benign	0.21
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: rs1254612410; hg19: chr19-34856291;