Genetic Variant NM_014485.3:c.559G>A (chr4-94299521-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014485.3(HPGDS):c.559G>A(p.Val187Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0058 in 1,613,422 control chromosomes in the GnomAD database, including 133 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 49 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 84 hom. )

Consequence

HPGDS
NM_014485.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.39

Publications

11 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00199157).

BP6

Variant 4-94299521-C-T is Benign according to our data. Variant chr4-94299521-C-T is described in ClinVar as Benign. ClinVar VariationId is 790394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0172 (2609/151794) while in subpopulation AFR AF = 0.0484 (2000/41334). AF 95% confidence interval is 0.0466. There are 49 homozygotes in GnomAd4. There are 1254 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 49 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014485.3. 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
	HPGDS	NM_014485.3	MANE Select	c.559G>A	p.Val187Ile	missense	Exon 6 of 6	NP_055300.1	A0A384P5J0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPGDS	ENST00000295256.10	TSL:1 MANE Select	c.559G>A	p.Val187Ile	missense	Exon 6 of 6	ENSP00000295256.5	O60760
	HPGDS	ENST00000944232.1		c.466G>A	p.Val156Ile	missense	Exon 5 of 5	ENSP00000614291.1

Frequencies

GnomAD3 genomes

AF:

0.0172

AC:

2602

AN:

151676

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0138

Gnomad ASJ

AF:

0.0113

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.00561

Gnomad FIN

AF:

0.00180

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.00356

Gnomad OTH

AF:

0.0249

GnomAD2 exomes

AF:

0.00755

AC:

1897

AN:

251218

AF XY:

0.00667

show subpopulations

Gnomad AFR exome

AF:

0.0487

Gnomad AMR exome

AF:

0.00775

Gnomad ASJ exome

AF:

0.0105

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00254

Gnomad NFE exome

AF:

0.00404

Gnomad OTH exome

AF:

0.0124

GnomAD4 exome

AF:

0.00462

AC:

6746

AN:

1461628

Hom.:

Cov.:

AF XY:

0.00455

AC XY:

3308

AN XY:

727112

show subpopulations

African (AFR)

AF:

0.0516

AC:

1726

AN:

33480

American (AMR)

AF:

0.00872

AC:

390

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0108

AC:

281

AN:

26124

East Asian (EAS)

AF:

0.000176

AC:

AN:

39692

South Asian (SAS)

AF:

0.00480

AC:

414

AN:

86216

European-Finnish (FIN)

AF:

0.00221

AC:

118

AN:

53414

Middle Eastern (MID)

AF:

0.0472

AC:

272

AN:

5762

European-Non Finnish (NFE)

AF:

0.00271

AC:

3008

AN:

1111852

Other (OTH)

AF:

0.00878

AC:

530

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

308

616

923

1231

1539

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

264

396

528

660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0172

AC:

2609

AN:

151794

Hom.:

Cov.:

AF XY:

0.0169

AC XY:

1254

AN XY:

74188

show subpopulations

African (AFR)

AF:

0.0484

AC:

2000

AN:

41334

American (AMR)

AF:

0.0138

AC:

210

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.0113

AC:

AN:

3462

East Asian (EAS)

AF:

0.000195

AC:

AN:

5124

South Asian (SAS)

AF:

0.00562

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00180

AC:

AN:

10542

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00356

AC:

242

AN:

67980

Other (OTH)

AF:

0.0251

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

130

260

389

519

649

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00852

Hom.:

Bravo

AF:

0.0193

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.0461

AC:

203

ESP6500EA

AF:

0.00547

AC:

ExAC

AF:

0.00834

AC:

1013

Asia WGS

AF:

0.00577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.17

DEOGEN2

Benign

0.031

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.36

MetaRNN

Benign

0.0020

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-1.9

PhyloP100

3.4

PrimateAI

Uncertain

0.52

PROVEAN

Benign

0.81

REVEL

Benign

0.14

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.23

MVP

0.081

MPC

0.0089

ClinPred

0.013

GERP RS

5.7

Varity_R

0.046

gMVP

0.27

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over