rs752119540

Variant names:

• chr19-34364991-C-A
• rs752119540
• NM_001289789.1:c.82C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-34364991-C-A
• chr19-34364991-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001289789.1(GPI):​c.82C>A​(p.Gln28Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000724 in 1,380,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: GPI NM_001289789.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.704
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08086696).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001289789.1. 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_001289789.1		c.82C>A	p.Gln28Lys	missense	Exon 1 of 19	NP_001276718.1	A0A2U3TZU2
	GPI	NM_001440422.1		c.82C>A	p.Gln28Lys	missense	Exon 2 of 20	NP_001427351.1
	GPI	NM_001184722.1		c.82C>A	p.Gln28Lys	missense	Exon 1 of 18	NP_001171651.1	P06744-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPI	ENST00000415930.8	TSL:2	c.82C>A	p.Gln28Lys	missense	Exon 1 of 19	ENSP00000405573.3	A0A2U3TZU2
	GPI	ENST00000588991.7	TSL:2	c.82C>A	p.Gln28Lys	missense	Exon 1 of 18	ENSP00000465858.3	P06744-2
	GPI	ENST00000592277.5	TSL:4	c.82C>A	p.Gln28Lys	missense	Exon 2 of 6	ENSP00000466191.1	K7ELR7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000762 AC: 1 AN: 131216 AF XY: 0.0000140

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.24e-7 AC: 1 AN: 1380290 Hom.: 0 Cov.: 30 AF XY: 0.00000147 AC XY: 1 AN XY: 681030

African (AFR) AF: 0.00 AC: 0 AN: 31414

American (AMR) AF: 0.00 AC: 0 AN: 35424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25120

East Asian (EAS) AF: 0.00 AC: 0 AN: 35482

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077024

Other (OTH) AF: 0.00 AC: 0 AN: 57756

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000576 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	6.3
DANN	Benign	0.67
DEOGEN2	Benign	0.0052	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.51	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.081	T
MetaSVM	Uncertain	-0.18	T
PhyloP100		0.70
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.13
Sift	Benign	0.045	D
Sift4G	Pathogenic	0.0	D
Vest4		0.29
MVP		0.55
MPC		0.57
ClinPred		0.062	T
GERP RS		1.1
PromoterAI		0.077	Neutral
gMVP		0.21
Mutation Taster		=94/6	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs752119540; hg19: chr19-34855896;