NM_000175.5:c.48dupG

Variant names:

• chr19-34365312-T-TG
• NM_000175.5:c.48dupG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000175.5(GPI):​c.48dupG​(p.Tyr17ValfsTer72) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GPI NM_000175.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.78
• 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: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 27 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-34365312-T-TG is Pathogenic according to our data. Variant chr19-34365312-T-TG is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3779707.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000175.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPI	NM_000175.5	MANE Select	c.48dupG	p.Tyr17ValfsTer72	frameshift	Exon 1 of 18	NP_000166.2
	GPI	NM_001289789.1		c.165dupG	p.Tyr56ValfsTer72	frameshift	Exon 2 of 19	NP_001276718.1	A0A2U3TZU2
	GPI	NM_001440422.1		c.165dupG	p.Tyr56ValfsTer72	frameshift	Exon 3 of 20	NP_001427351.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPI	ENST00000356487.11	TSL:1 MANE Select	c.48dupG	p.Tyr17ValfsTer72	frameshift	Exon 1 of 18	ENSP00000348877.3	P06744-1
	GPI	ENST00000415930.8	TSL:2	c.165dupG	p.Tyr56ValfsTer72	frameshift	Exon 2 of 19	ENSP00000405573.3	A0A2U3TZU2
	GPI	ENST00000899688.1		c.48dupG	p.Tyr17ValfsTer86	frameshift	Exon 1 of 18	ENSP00000569747.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hemolytic anemia due to glucophosphate isomerase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.8

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

hg19: chr19-34856217;