rs577045722
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000860.6(HPGD):c.1A>T(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000444 in 1,575,694 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 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000042 ( 0 hom. )
Consequence
HPGD
NM_000860.6 start_lost
NM_000860.6 start_lost
Scores
6
7
3
Clinical Significance
Conservation
PhyloP100: 6.01
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 4-174522451-T-A is Pathogenic according to our data. Variant chr4-174522451-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 156026.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HPGD | NM_000860.6 | c.1A>T | p.Met1? | start_lost | 1/7 | ENST00000296522.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HPGD | ENST00000296522.11 | c.1A>T | p.Met1? | start_lost | 1/7 | 1 | NM_000860.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152110Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000551 AC: 1AN: 181474Hom.: 0 AF XY: 0.0000101 AC XY: 1AN XY: 99260
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GnomAD4 exome AF: 0.00000421 AC: 6AN: 1423584Hom.: 0 Cov.: 31 AF XY: 0.00000426 AC XY: 3AN XY: 704832
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152110Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74298
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hypertrophic osteoarthropathy, primary, autosomal recessive, 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2009 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 01, 2023 | This sequence change affects the initiator methionine of the HPGD mRNA. The next in-frame methionine is located at codon 122. This variant is present in population databases (rs577045722, gnomAD 0.001%). Disruption of the initiator codon has been observed in individual(s) with primary hypertrophic osteoarthropathy (PMID: 19306095). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 156026). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Benign
DEOGEN2
Uncertain
T;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D
PROVEAN
Uncertain
N;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;T;D;T
Sift4G
Benign
T;D;T;T;T
Polyphen
P;.;.;.;P
Vest4
MutPred
Loss of methylation at K6 (P = 0.0681);Loss of methylation at K6 (P = 0.0681);Loss of methylation at K6 (P = 0.0681);Loss of methylation at K6 (P = 0.0681);Loss of methylation at K6 (P = 0.0681);
MVP
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at