rs34124298

Variant names:

• chr4-94302198-A-G
• rs34124298
• NM_014485.3:c.383T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 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=0.0071651638).
• 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. GnomAdExome4 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 GnomAdExome4. There are 2366 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPGDS	NM_014485.3	c.383T>C	p.Met128Thr	missense_variant	Exon 5 of 6	ENST00000295256.10	NP_055300.1
HPGDS	XM_005262932.4	c.290T>C	p.Met97Thr	missense_variant	Exon 4 of 5		XP_005262989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPGDS	ENST00000295256.10	c.383T>C	p.Met128Thr	missense_variant	Exon 5 of 6	1	NM_014485.3	ENSP00000295256.5

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

GnomAD2 exomes AF: 0.00439 AC: 1103 AN: 250982 AF XY: 0.00430

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 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

African (AFR) AF: 0.0143 AC: 479 AN: 33420

American (AMR) AF: 0.00557 AC: 249 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00675 AC: 176 AN: 26092

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39588

South Asian (SAS) AF: 0.00472 AC: 407 AN: 86164

European-Finnish (FIN) AF: 0.00215 AC: 115 AN: 53404

Middle Eastern (MID) AF: 0.0432 AC: 249 AN: 5764

European-Non Finnish (NFE) AF: 0.00237 AC: 2637 AN: 1111064

Other (OTH) AF: 0.00564 AC: 340 AN: 60324

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

African (AFR) AF: 0.0127 AC: 526 AN: 41544

American (AMR) AF: 0.00871 AC: 133 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00559 AC: 27 AN: 4832

European-Finnish (FIN) AF: 0.00169 AC: 18 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00318 AC: 216 AN: 68004

Other (OTH) AF: 0.0156 AC: 33 AN: 2114

Alfa AF: 0.00496 Hom.: 12

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

Jun 08, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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
PhyloP100		5.8
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
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs34124298; hg19: chr4-95223349;