rs587777719
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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
NM_000860.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.00
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 18 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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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 | 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 | c.310_311del | p.Leu104AlafsTer3 | frameshift_variant | 3/7 | 1 | NM_000860.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 151994Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000519 AC: 13AN: 250330Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135312
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GnomAD4 exome AF: 0.0000159 AC: 22AN: 1383468Hom.: 0 AF XY: 0.0000159 AC XY: 11AN XY: 693516
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152112Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74340
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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 | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | - | - - |
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 | literature only | Yale Center for Mendelian Genomics, Yale University | May 12, 2014 | - - |
HPGD-related disorder Pathogenic:2
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 (Tüysüz 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. - |
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. - |
not provided Pathogenic:2
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. - |
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) - |
Computational scores
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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