chr4-94302198-A-G

Position:

• chr4-94302198-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014485.3(HPGDS):​c.383T>C​(p.Met128Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0035 in 1,612,780 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (36 hom.)
• Consequence: HPGDS NM_014485.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.75

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071651638).
• BP6: Variant 4-94302198-A-G is Benign according to our data. Variant chr4-94302198-A-G is described in ClinVar as [Benign]. Clinvar id is 790395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00319 (4653/1460522) while in subpopulation MID AF= 0.0432 (249/5764). AF 95% confidence interval is 0.0388. There are 36 homozygotes in gnomad4_exome. There are 2366 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPGDS	NM_014485.3	c.383T>C	p.Met128Thr	missense_variant	5/6	ENST00000295256.10
HPGDS	XM_005262932.4	c.290T>C	p.Met97Thr	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPGDS	ENST00000295256.10	c.383T>C	p.Met128Thr	missense_variant	5/6	1	NM_014485.3	P1

Frequencies

GnomAD3 genomes AF: 0.00651 AC: 990 AN: 152140 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00872

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00558

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.00318

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00439 AC: 1103 AN: 250982 Hom.: 6 AF XY: 0.00430 AC XY: 583 AN XY: 135634

Gnomad AFR exome AF: 0.0134

Gnomad AMR exome AF: 0.00495

Gnomad ASJ exome AF: 0.00655

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00448

Gnomad FIN exome AF: 0.00254

Gnomad NFE exome AF: 0.00353

Gnomad OTH exome AF: 0.00915

GnomAD4 exome AF: 0.00319 AC: 4653 AN: 1460522 Hom.: 36 Cov.: 29 AF XY: 0.00326 AC XY: 2366 AN XY: 726588

Gnomad4 AFR exome AF: 0.0143

Gnomad4 AMR exome AF: 0.00557

Gnomad4 ASJ exome AF: 0.00675

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00472

Gnomad4 FIN exome AF: 0.00215

Gnomad4 NFE exome AF: 0.00237

Gnomad4 OTH exome AF: 0.00564

GnomAD4 genome AF: 0.00653 AC: 995 AN: 152258 Hom.: 4 Cov.: 32 AF XY: 0.00685 AC XY: 510 AN XY: 74454

Gnomad4 AFR AF: 0.0127

Gnomad4 AMR AF: 0.00871

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00559

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.00318

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.00467 Hom.: 7

Bravo AF: 0.00740

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0125 AC: 55

ESP6500EA AF: 0.00477 AC: 41

ExAC AF: 0.00471 AC: 572

Asia WGS AF: 0.00405 AC: 14 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 08, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.073	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.061
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.14	N
MutationTaster	Benign	0.77	N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.14
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.030	D
Polyphen		0.013	B
Vest4		0.51
MVP		0.20
MPC		0.014
ClinPred		0.079	T
GERP RS		5.5
Varity_R		0.71
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34124298; hg19: chr4-95223349;