19-34377737-A-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_000175.5(GPI):​c.489A>T​(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 0.00000434 in 1,613,414 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. G163G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GPI NM_000175.5 splice_region, synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 19-34377737-A-T is Benign according to our data. Variant chr19-34377737-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 740383.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.807 with no splicing effect.

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

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151724 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461690 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727158

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111844

Other (OTH) AF: 0.0000331 AC: 2 AN: 60386

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151724 Hom.: 0 Cov.: 30 AF XY: 0.0000405 AC XY: 3 AN XY: 74126

African (AFR) AF: 0.00 AC: 0 AN: 41224

American (AMR) AF: 0.000263 AC: 4 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67960

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 850

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.5
DANN	Benign	0.70
PhyloP100		-0.81
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7

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;