4-174517983-CAG-C

Variant names:

• chr4-174517983-CAG-C
• rs587777719
• NM_000860.6:c.310_311delCT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000860.6(HPGD):​c.310_311delCT​(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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 8.00
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• hypertrophic osteoarthropathy, primary, autosomal recessive, 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• cranio-osteoarthropathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• pachydermoperiostosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• isolated congenital digital clubbing

  Inheritance: Unknown, AD, AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 4-174517983-CAG-C is Pathogenic according to our data. Variant chr4-174517983-CAG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 156027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000860.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPGD	NM_000860.6	MANE Select	c.310_311delCT	p.Leu104AlafsTer3	frameshift	Exon 3 of 7	NP_000851.2
	HPGD	NM_001145816.3		c.310_311delCT	p.Leu104AlafsTer3	frameshift	Exon 3 of 6	NP_001139288.1
	HPGD	NM_001363574.2		c.310_311delCT	p.Leu104AlafsTer3	frameshift	Exon 3 of 5	NP_001350503.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPGD	ENST00000296522.11	TSL:1 MANE Select	c.310_311delCT	p.Leu104AlafsTer3	frameshift	Exon 3 of 7	ENSP00000296522.6
	HPGD	ENST00000296521.11	TSL:1	c.310_311delCT	p.Leu104AlafsTer3	frameshift	Exon 3 of 6	ENSP00000296521.7
	HPGD	ENST00000542498.5	TSL:1	c.310_311delCT	p.Leu104AlafsTer3	frameshift	Exon 3 of 5	ENSP00000443644.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151994 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000519 AC: 13 AN: 250330 AF XY: 0.0000443

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000159 AC: 22 AN: 1383468 Hom.: 0 AF XY: 0.0000159 AC XY: 11 AN XY: 693516

African (AFR) AF: 0.00 AC: 0 AN: 31932

American (AMR) AF: 0.00 AC: 0 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25600

East Asian (EAS) AF: 0.000408 AC: 16 AN: 39196

South Asian (SAS) AF: 0.00 AC: 0 AN: 84498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5608

European-Non Finnish (NFE) AF: 0.00000576 AC: 6 AN: 1041070

Other (OTH) AF: 0.00 AC: 0 AN: 57612

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152112 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74340

African (AFR) AF: 0.00 AC: 0 AN: 41534

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67954

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000529

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic osteoarthropathy, primary, autosomal recessive, 1 Pathogenic:5

Feb 18, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

May 12, 2014

Yale Center for Mendelian Genomics, Yale University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Prenatal Diagnosis Center, International Peace Maternity & Child Health Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Nov 07, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000156027 /PMID: 24533558). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

HPGD-related disorder Pathogenic:2

Apr 21, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Aug 22, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not provided Pathogenic:2

Oct 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Apr 11, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

Isolated congenital digital clubbing;C4551679:Hypertrophic osteoarthropathy, primary, autosomal recessive, 1 Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Null variant in a gene where loss of function (LOF) is a known mechanism of disease.;For recessive disorders, detected in trans with a pathogenic variant.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587777719; hg19: chr4-175439134;