rs587777719

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000860.6(HPGD):c.310_311del(p.Leu104AlafsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000163 in 1,535,580 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

HPGD
NM_000860.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 8.00

Variant links:

Genes affected

HPGD (HGNC:5154): (15-hydroxyprostaglandin dehydrogenase) This gene encodes a member of the short-chain nonmetalloenzyme alcohol dehydrogenase protein family. The encoded enzyme is responsible for the metabolism of prostaglandins, which function in a variety of physiologic and cellular processes such as inflammation. Mutations in this gene result in primary autosomal recessive hypertrophic osteoarthropathy and cranioosteoarthropathy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

HPGD links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-174517983-CAG-C is Pathogenic according to our data. Variant chr4-174517983-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 156027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPGD	NM_000860.6 linkuse as main transcript	c.310_311del	p.Leu104AlafsTer3	frameshift_variant	3/7	ENST00000296522.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPGD	ENST00000296522.11 linkuse as main transcript	c.310_311del	p.Leu104AlafsTer3	frameshift_variant	3/7	1	NM_000860.6	P1	P15428-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000519

AC:

AN:

250330

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135312

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000599

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000159

AC:

AN:

1383468

Hom.:

AF XY:

0.0000159

AC XY:

AN XY:

693516

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000408

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000576

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000529

Asia WGS

AF:

0.000578

AC:

AN:

3476

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic osteoarthropathy, primary, autosomal recessive, 1

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	May 12, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 18, 2014	- -
Pathogenic, no assertion criteria provided	literature only	Prenatal Diagnosis Center, International Peace Maternity & Child Health Hospital	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	-	- -

HPGD-related disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 21, 2023	The HPGD c.310_311delCT variant is predicted to result in a frameshift and premature protein termination (p.Leu104Alafs*3). This variant has been reported in multiple individuals with primary hypertrophic osteoarthropathy in the homozygous or compound heterozygous state (see for example, Erken et al 2015. PubMed ID: 24533558; Tüysüz B et al 2014. PubMed ID: 24816859; Lu et al. 2022. PubMed ID: 35813463). This variant is reported in 0.060% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-175439134-CAG-C). Frameshift variants in HPGD are expected to be pathogenic. This variant is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 22, 2018	The HPGD c.310_311delCT (p.Leu104AlafsTer3) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Leu104AlafsTer3 variant has been identified in 13 individuals with primary hypertrophic osteoarthropathy, including in a homozygous state in ten probands, in a compound heterozygous state in one proband, and in a heterozygous state in two probands in whom a second variant was not identified (TÃ¼ysÃ¼z et al. 2014; Erken et al. 2015; Yuan et al. 2015). The p.Leu104AlafsTer3 variant was also found in a heterozygous state in nine unaffected relatives of the probands. The p.Leu104AlafsTer3 variant was absent from 236 controls and is reported at a frequency of 0.00061 in the East Asian population of the Exome Aggregation Consortium. Based on the evidence, the p.Leu104AlafsTer3 is classified as pathogenic for HPGD-related disorders. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 11, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34426522, 29652982, 25863089, 28253600, 30215240, 30292630, 24816859, 24533558, 31063976) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 25, 2023	This sequence change creates a premature translational stop signal (p.Leu104Alafs*3) in the HPGD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HPGD are known to be pathogenic (PMID: 18500342, 19568269, 24533558, 24816859). This variant is present in population databases (rs587777719, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with primary hypertrophic osteoarthropathy (PMID: 24533558). ClinVar contains an entry for this variant (Variation ID: 156027). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over