4-94308699-T-C

Position:

• chr4-94308699-T-C

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.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. 14/20 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 NM_014485.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.342

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=0.008059353).
• BP6: Variant 4-94308699-T-C is Benign according to our data. Variant chr4-94308699-T-C is described in ClinVar as [Benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPGDS	NM_014485.3	c.271A>G	p.Ile91Val	missense_variant	4/6	ENST00000295256.10
HPGDS	XM_005262932.4	c.178A>G	p.Ile60Val	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPGDS	ENST00000295256.10	c.271A>G	p.Ile91Val	missense_variant	4/6	1	NM_014485.3	P1
HPGDS	ENST00000514774.1	n.351A>G		non_coding_transcript_exon_variant	4/5	4

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

GnomAD3 exomes AF: 0.00487 AC: 1216 AN: 249878 Hom.: 8 AF XY: 0.00455 AC XY: 615 AN XY: 135058

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 SAS exome AF: 0.00441

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

Gnomad4 AFR exome AF: 0.0223

Gnomad4 AMR exome AF: 0.00570

Gnomad4 ASJ exome AF: 0.00672

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00466

Gnomad4 FIN exome AF: 0.00218

Gnomad4 NFE exome AF: 0.00237

Gnomad4 OTH exome AF: 0.00621

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

Gnomad4 AFR AF: 0.0199

Gnomad4 AMR AF: 0.00949

Gnomad4 ASJ AF: 0.00722

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00560

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.00325

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.00491 Hom.: 7

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

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

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	N
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

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

LitVar

Other links and lift over

dbSNP: rs61752528; hg19: chr4-95229850;