NM_000175.5:c.213+13T>C

Variant names:

• chr19-34366448-T-C
• rs1427928975
• NM_000175.5:c.213+13T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_000175.5(GPI):​c.213+13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000698 in 1,432,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: GPI NM_000175.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.43
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 19-34366448-T-C is Benign according to our data. Variant chr19-34366448-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3694772.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.213+13T>C		intron	N/A	NP_000166.2
	GPI	NM_001289789.1		c.330+13T>C		intron	N/A	NP_001276718.1	A0A2U3TZU2
	GPI	NM_001440422.1		c.330+13T>C		intron	N/A	NP_001427351.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPI	ENST00000356487.11	TSL:1 MANE Select	c.213+13T>C		intron	N/A	ENSP00000348877.3	P06744-1
	GPI	ENST00000415930.8	TSL:2	c.330+13T>C		intron	N/A	ENSP00000405573.3	A0A2U3TZU2
	GPI	ENST00000899688.1		c.255+13T>C		intron	N/A	ENSP00000569747.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000698 AC: 10 AN: 1432286 Hom.: 0 Cov.: 25 AF XY: 0.00000420 AC XY: 3 AN XY: 714344

African (AFR) AF: 0.00 AC: 0 AN: 32820

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25974

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39590

South Asian (SAS) AF: 0.00 AC: 0 AN: 85698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00000737 AC: 8 AN: 1085012

Other (OTH) AF: 0.0000168 AC: 1 AN: 59390

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	-0.74
CADD	Benign	5.2
DANN	Benign	0.55
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1427928975; hg19: chr19-34857353;