rs121434480

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000860.6(HPGD):c.418G>C(p.Ala140Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000278 in 1,580,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

HPGD
NM_000860.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 5.81

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

PP5

Variant 4-174508699-C-G is Pathogenic according to our data. Variant chr4-174508699-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 7917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-174508699-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPGD	NM_000860.6 linkuse as main transcript	c.418G>C	p.Ala140Pro	missense_variant	4/7	ENST00000296522.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPGD	ENST00000296522.11 linkuse as main transcript	c.418G>C	p.Ala140Pro	missense_variant	4/7	1	NM_000860.6	P1	P15428-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152068

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:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251282

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135826

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:

0.000621

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000294

AC:

AN:

1428332

Hom.:

Cov.:

AF XY:

0.0000449

AC XY:

AN XY:

712766

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000479

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000169

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152068

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74284

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:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic osteoarthropathy, primary, autosomal recessive, 1

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 10, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects HPGD function (PMID: 18500342). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 7917). This missense change has been observed in individuals with clinical features of hypertrophic osteoarthropathy (PMID: 18500342, 32282352). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121434480, gnomAD 0.06%). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 140 of the HPGD protein (p.Ala140Pro). -

Cranioosteoarthropathy

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.40

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;.;.;.;.;D;.;.

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

D;D;T;D;.;D;D;T

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.96

D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

3.6

H;.;H;H;.;.;.;.

MutationTaster

Benign

1.0

A;A;A;A;A;A;A

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-4.1

D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0060

D;D;D;D;D;D;D;D

Sift4G

Benign

0.067

T;D;T;T;D;.;T;D

Polyphen

1.0

D;.;.;.;.;.;.;D

Vest4

0.95

MutPred

0.93

Loss of catalytic residue at A140 (P = 0.0319);.;Loss of catalytic residue at A140 (P = 0.0319);Loss of catalytic residue at A140 (P = 0.0319);.;.;.;Loss of catalytic residue at A140 (P = 0.0319);

MVP

0.98

MPC

0.23

ClinPred

0.90

GERP RS

6.0

Varity_R

0.98

gMVP

0.99

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

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