Genetic Variant HPGDS:p.Ile67Thr (chr4-94317899-A-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_014485.3(HPGDS):c.200T>C(p.Ile67Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,458,882 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

HPGDS
NM_014485.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.72

Variant links:

Genes affected

HPGDS (HGNC:17890): (hematopoietic prostaglandin D synthase) Prostaglandin-D synthase is a sigma class glutathione-S-transferase family member. The enzyme catalyzes the conversion of PGH2 to PGD2 and plays a role in the production of prostanoids in the immune system and mast cells. The presence of this enzyme can be used to identify the differentiation stage of human megakaryocytes. [provided by RefSeq, Jul 2008]

HPGDS links:

ENSG00000287552 (HGNC:):

ENSG00000287552 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.947

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPGDS	NM_014485.3 link	c.200T>C	p.Ile67Thr	missense_variant	Exon 3 of 6	ENST00000295256.10	NP_055300.1	O60760A0A384P5J0
HPGDS	XM_005262932.4 link	c.134-9156T>C		intron_variant	Intron 2 of 4		XP_005262989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HPGDS	ENST00000295256.10 link	c.200T>C	p.Ile67Thr	missense_variant	Exon 3 of 6	1	NM_014485.3	ENSP00000295256.5	O60760
HPGDS	ENST00000514774.1 link	n.280T>C		non_coding_transcript_exon_variant	Exon 3 of 5	4
ENSG00000287552	ENST00000667612.1 link	n.2414A>G		non_coding_transcript_exon_variant	Exon 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1458882

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725812

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.200T>C (p.I67T) alteration is located in exon 3 (coding exon 2) of the HPGDS gene. This alteration results from a T to C substitution at nucleotide position 200, causing the isoleucine (I) at amino acid position 67 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.040

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

-0.28

MutationAssessor

Pathogenic

4.4

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-4.0

REVEL

Uncertain

0.50

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.85

MutPred

0.82

Loss of stability (P = 0.0098);

MVP

0.36

MPC

0.052

ClinPred

1.0

GERP RS

5.5

Varity_R

0.73

gMVP

0.83

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over