Variant chr4-174521984-CAG-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000296522.11(HPGD):c.175_176del(p.Leu59ValfsTer8) variant causes a frameshift change. The variant allele was found at a frequency of 0.000198 in 1,614,010 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 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

HPGD
ENST00000296522.11 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 4.50

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 4-174521984-CAG-C is Pathogenic according to our data. Variant chr4-174521984-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 7919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPGD	NM_000860.6 linkuse as main transcript	c.175_176del	p.Leu59ValfsTer8	frameshift_variant	2/7	ENST00000296522.11	NP_000851.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPGD	ENST00000296522.11 linkuse as main transcript	c.175_176del	p.Leu59ValfsTer8	frameshift_variant	2/7	1	NM_000860.6	ENSP00000296522	P1	P15428-1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152180

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000155

AC:

AN:

251456

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000204

AC:

298

AN:

1461830

Hom.:

AF XY:

0.000208

AC XY:

151

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000562

Gnomad4 NFE exome

AF:

0.000229

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000138

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000376

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.000113

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic osteoarthropathy, primary, autosomal recessive, 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2008

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 04, 2023

This sequence change creates a premature translational stop signal (p.Leu59Valfs*8) 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 (rs548208942, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with primary hypertrophic osteoarthropathy (PMID: 18500342). ClinVar contains an entry for this variant (Variation ID: 7919). For these reasons, this variant has been classified as Pathogenic. -

Isolated congenital digital clubbing

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Oct 02, 2019

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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