19-34365325-A-C

Variant names:

• chr19-34365325-A-C
• rs137853586
• NM_000175.5:c.59A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000175.5(GPI):​c.59A>C​(p.His20Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000278 in 1,439,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: GPI NM_000175.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.17
• Publications: 10 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: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 19-34365325-A-C is Pathogenic according to our data. Variant chr19-34365325-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 13644.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPI	NM_000175.5	c.59A>C	p.His20Pro	missense_variant	Exon 1 of 18	ENST00000356487.11	NP_000166.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPI	ENST00000356487.11	c.59A>C	p.His20Pro	missense_variant	Exon 1 of 18	1	NM_000175.5	ENSP00000348877.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000131 AC: 3 AN: 228814 AF XY: 0.0000159

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: 0.0000286

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000278 AC: 4 AN: 1439082 Hom.: 0 Cov.: 33 AF XY: 0.00000419 AC XY: 3 AN XY: 716354

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30700

American (AMR) AF: 0.00 AC: 0 AN: 43172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25348

East Asian (EAS) AF: 0.00 AC: 0 AN: 37368

South Asian (SAS) AF: 0.00 AC: 0 AN: 84322

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00000363 AC: 4 AN: 1102890

Other (OTH) AF: 0.00 AC: 0 AN: 59300

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000173310), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00136 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hemolytic anemia due to glucophosphate isomerase deficiency Pathogenic:1

Oct 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	21
DANN	Benign	0.48
DEOGEN2	Benign	0.098	.;.;T;.;.;.;T;D;T;T;.;D
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	T;T;.;T;T;T;.;.;.;.;T;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.3	.;.;.;.;.;.;.;M;.;.;.;M
PhyloP100		4.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.9	.;.;.;.;D;.;.;.;.;.;.;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.028	.;.;.;.;D;.;.;.;.;.;.;D
Sift4G	Benign	0.066	T;T;T;.;T;.;T;.;T;T;T;T
Polyphen		0.0	.;.;.;.;.;.;.;B;.;.;.;B
Vest4		0.69, 0.68
MutPred		0.82		.;.;.;.;.;.;Gain of glycosylation at H20 (P = 0.0199);Gain of glycosylation at H20 (P = 0.0199);Gain of glycosylation at H20 (P = 0.0199);Gain of glycosylation at H20 (P = 0.0199);Gain of glycosylation at H20 (P = 0.0199);Gain of glycosylation at H20 (P = 0.0199);
MVP		0.93
MPC		0.96
ClinPred		0.14	T
GERP RS		3.8
PromoterAI		0.042	Neutral
Varity_R		0.83
gMVP		0.76
Mutation Taster		=11/89	disease causing (ClinVar)

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: rs137853586; hg19: chr19-34856230;