rs9312555

Positions:

• chr4-174490802-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000860.6(HPGD):​c.*1154T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 152,246 control chromosomes in the GnomAD database, including 2,861 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2859 hom., cov: 32)
  • Exomes 𝑓: 0.12 (2 hom.)
• Consequence: HPGD NM_000860.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.98

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 4-174490802-A-G is Benign according to our data. Variant chr4-174490802-A-G is described in ClinVar as [Benign]. Clinvar id is 348180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.498 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPGD	NM_000860.6	c.*1154T>C		3_prime_UTR_variant	7/7	ENST00000296522.11	NP_000851.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPGD	ENST00000296522.11	c.*1154T>C		3_prime_UTR_variant	7/7	1	NM_000860.6	ENSP00000296522	P1
HPGD	ENST00000542498.5	c.*1282T>C		3_prime_UTR_variant	5/5	1		ENSP00000443644
HPGD	ENST00000541923.5	c.*1154T>C		3_prime_UTR_variant	6/6	2		ENSP00000438017

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26365 AN: 151992 Hom.: 2855 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.514

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.175

GnomAD4 exome AF: 0.116 AC: 16 AN: 138 Hom.: 2 Cov.: 0 AF XY: 0.132 AC XY: 10 AN XY: 76

Gnomad4 EAS exome AF: 0.116

GnomAD4 genome AF: 0.173 AC: 26376 AN: 152108 Hom.: 2859 Cov.: 32 AF XY: 0.177 AC XY: 13187 AN XY: 74358

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.281

Gnomad4 ASJ AF: 0.163

Gnomad4 EAS AF: 0.515

Gnomad4 SAS AF: 0.170

Gnomad4 FIN AF: 0.160

Gnomad4 NFE AF: 0.151

Gnomad4 OTH AF: 0.173

Alfa AF: 0.162 Hom.: 2892

Bravo AF: 0.183

Asia WGS AF: 0.286 AC: 992 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic osteoarthropathy, primary, autosomal recessive, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Isolated congenital digital clubbing Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.077
DANN	Benign	0.36

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

Other links and lift over

dbSNP: rs9312555; hg19: chr4-175411953;