rs61752528

Variant names:

• chr4-94308699-T-C
• rs61752528
• NM_014485.3:c.271A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000295256.10(HPGDS):​c.271A>G​(p.Ile91Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 1,609,360 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0086 (10 hom., cov: 31)
  • Exomes 𝑓: 0.0034 (37 hom.)
• Consequence: HPGDS ENST00000295256.10 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.342
• Publications: 8 publications found

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.008059353).
• BP6: Variant 4-94308699-T-C is Benign according to our data. Variant chr4-94308699-T-C is described in ClinVar as Benign. ClinVar VariationId is 790396.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 = 0.00863 (1313/152192) while in subpopulation AFR AF = 0.0199 (825/41526). AF 95% confidence interval is 0.0187. There are 10 homozygotes in GnomAd4. There are 663 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000295256.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPGDS	NM_014485.3	MANE Select	c.271A>G	p.Ile91Val	missense	Exon 4 of 6	NP_055300.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPGDS	ENST00000295256.10	TSL:1 MANE Select	c.271A>G	p.Ile91Val	missense	Exon 4 of 6	ENSP00000295256.5
	HPGDS	ENST00000514774.1	TSL:4	n.351A>G		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes AF: 0.00859 AC: 1307 AN: 152074 Hom.: 10 Cov.: 31

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00951

Gnomad ASJ AF: 0.00722

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.00325

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.00487 AC: 1216 AN: 249878 AF XY: 0.00455

Gnomad AFR exome AF: 0.0209

Gnomad AMR exome AF: 0.00492

Gnomad ASJ exome AF: 0.00655

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00254

Gnomad NFE exome AF: 0.00351

Gnomad OTH exome AF: 0.00937

GnomAD4 exome AF: 0.00339 AC: 4943 AN: 1457168 Hom.: 37 Cov.: 28 AF XY: 0.00344 AC XY: 2497 AN XY: 724968

African (AFR) AF: 0.0223 AC: 744 AN: 33328

American (AMR) AF: 0.00570 AC: 254 AN: 44536

Ashkenazi Jewish (ASJ) AF: 0.00672 AC: 175 AN: 26048

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39532

South Asian (SAS) AF: 0.00466 AC: 400 AN: 85748

European-Finnish (FIN) AF: 0.00218 AC: 116 AN: 53330

Middle Eastern (MID) AF: 0.0446 AC: 256 AN: 5744

European-Non Finnish (NFE) AF: 0.00237 AC: 2623 AN: 1108704

Other (OTH) AF: 0.00621 AC: 374 AN: 60198

GnomAD4 genome AF: 0.00863 AC: 1313 AN: 152192 Hom.: 10 Cov.: 31 AF XY: 0.00891 AC XY: 663 AN XY: 74426

African (AFR) AF: 0.0199 AC: 825 AN: 41526

American (AMR) AF: 0.00949 AC: 145 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00722 AC: 25 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00560 AC: 27 AN: 4822

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10608

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.00325 AC: 221 AN: 67990

Other (OTH) AF: 0.0170 AC: 36 AN: 2116

Alfa AF: 0.00571 Hom.: 16

Bravo AF: 0.0100

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0197 AC: 87

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.00530 AC: 644

Asia WGS AF: 0.00491 AC: 17 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.9
DANN	Benign	0.75
DEOGEN2	Benign	0.045	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0081	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.34
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.065
Sift	Benign	0.30	T
Sift4G	Benign	0.37	T
Polyphen		0.0	B
Vest4		0.27
MVP		0.076
MPC		0.0090
ClinPred		0.00017	T
GERP RS		-0.92
Varity_R		0.083
gMVP		0.40
Mutation Taster		=94/6	polymorphism

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: rs61752528; hg19: chr4-95229850;