NM_000175.5:c.489A>G

Variant names:

• chr19-34377737-A-G
• rs1801015
• NM_000175.5:c.489A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000175.5(GPI):​c.489A>G​(p.Gly163Gly) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0866 in 1,613,160 control chromosomes in the GnomAD database, including 9,609 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G163G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.15 (2932 hom., cov: 30)
  • Exomes 𝑓: 0.080 (6677 hom.)
• Consequence: GPI NM_000175.5 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.807
• Publications: 22 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 19-34377737-A-G is Benign according to our data. Variant chr19-34377737-A-G is described in ClinVar as Benign. ClinVar VariationId is 255472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.807 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.337 is higher than 0.05.

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.489A>G	p.Gly163Gly	splice_region synonymous	Exon 6 of 18	NP_000166.2
	GPI	NM_001289789.1		c.606A>G	p.Gly202Gly	splice_region synonymous	Exon 7 of 19	NP_001276718.1	A0A2U3TZU2
	GPI	NM_001440422.1		c.606A>G	p.Gly202Gly	splice_region synonymous	Exon 8 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.489A>G	p.Gly163Gly	splice_region synonymous	Exon 6 of 18	ENSP00000348877.3	P06744-1
	GPI	ENST00000415930.8	TSL:2	c.606A>G	p.Gly202Gly	splice_region synonymous	Exon 7 of 19	ENSP00000405573.3	A0A2U3TZU2
	GPI	ENST00000899688.1		c.531A>G	p.Gly177Gly	splice_region synonymous	Exon 6 of 18	ENSP00000569747.1

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23285 AN: 151678 Hom.: 2910 Cov.: 30

Gnomad AFR AF: 0.341

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.0927

Gnomad EAS AF: 0.198

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.0859

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0622

Gnomad OTH AF: 0.118

GnomAD2 exomes AF: 0.108 AC: 27032 AN: 251446 AF XY: 0.103

Gnomad AFR exome AF: 0.341

Gnomad AMR exome AF: 0.0835

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.202

Gnomad FIN exome AF: 0.0821

Gnomad NFE exome AF: 0.0627

Gnomad OTH exome AF: 0.0893

GnomAD4 exome AF: 0.0796 AC: 116352 AN: 1461364 Hom.: 6677 Cov.: 31 AF XY: 0.0803 AC XY: 58343 AN XY: 727010

African (AFR) AF: 0.350 AC: 11714 AN: 33450

American (AMR) AF: 0.0846 AC: 3783 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0992 AC: 2592 AN: 26136

East Asian (EAS) AF: 0.166 AC: 6574 AN: 39690

South Asian (SAS) AF: 0.142 AC: 12260 AN: 86246

European-Finnish (FIN) AF: 0.0881 AC: 4704 AN: 53416

Middle Eastern (MID) AF: 0.107 AC: 619 AN: 5764

European-Non Finnish (NFE) AF: 0.0610 AC: 67751 AN: 1111572

Other (OTH) AF: 0.105 AC: 6355 AN: 60368

GnomAD4 genome AF: 0.154 AC: 23349 AN: 151796 Hom.: 2932 Cov.: 30 AF XY: 0.155 AC XY: 11532 AN XY: 74228

African (AFR) AF: 0.342 AC: 14126 AN: 41326

American (AMR) AF: 0.105 AC: 1594 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.0927 AC: 321 AN: 3462

East Asian (EAS) AF: 0.197 AC: 1015 AN: 5160

South Asian (SAS) AF: 0.156 AC: 749 AN: 4802

European-Finnish (FIN) AF: 0.0859 AC: 906 AN: 10546

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0622 AC: 4225 AN: 67942

Other (OTH) AF: 0.120 AC: 252 AN: 2104

Alfa AF: 0.0918 Hom.: 850

Bravo AF: 0.160

Asia WGS AF: 0.227 AC: 791 AN: 3478

EpiCase AF: 0.0646

EpiControl AF: 0.0656

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Hemolytic anemia due to glucophosphate isomerase deficiency (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	7.0
DANN	Benign	0.61
PhyloP100		-0.81
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Mutation Taster		=97/3	polymorphism (auto)

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: rs1801015; hg19: chr19-34868642; COSMIC: COSV62894048; COSMIC: COSV62894048;