4-174490230-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000860.6(HPGD):c.*1726C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.785 in 151,706 control chromosomes in the GnomAD database, including 46,873 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.78 (46832 hom., cov: 32)
  • Exomes 𝑓: 0.78 (41 hom.)
• Consequence: HPGD NM_000860.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.398

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 4-174490230-G-A is Benign according to our data. Variant chr4-174490230-G-A is described in ClinVar as [Benign]. Clinvar id is 348168.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.8 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPGD	NM_000860.6	c.*1726C>T		3_prime_UTR_variant	7/7	ENST00000296522.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPGD	ENST00000296522.11	c.*1726C>T		3_prime_UTR_variant	7/7	1	NM_000860.6	P1
HPGD	ENST00000542498.5	c.*1854C>T		3_prime_UTR_variant	5/5	1
HPGD	ENST00000541923.5	c.*1726C>T		3_prime_UTR_variant	6/6	2

Frequencies

GnomAD3 genomes AF: 0.784 AC: 118814 AN: 151452 Hom.: 46786 Cov.: 32

Gnomad AFR AF: 0.807

Gnomad AMI AF: 0.737

Gnomad AMR AF: 0.739

Gnomad ASJ AF: 0.817

Gnomad EAS AF: 0.819

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.840

Gnomad MID AF: 0.718

Gnomad NFE AF: 0.781

Gnomad OTH AF: 0.780

GnomAD4 exome AF: 0.779 AC: 106 AN: 136 Hom.: 41 Cov.: 0 AF XY: 0.829 AC XY: 63 AN XY: 76

Gnomad4 EAS exome AF: 0.779

GnomAD4 genome AF: 0.785 AC: 118917 AN: 151570 Hom.: 46832 Cov.: 32 AF XY: 0.783 AC XY: 58004 AN XY: 74040

Gnomad4 AFR AF: 0.807

Gnomad4 AMR AF: 0.739

Gnomad4 ASJ AF: 0.817

Gnomad4 EAS AF: 0.819

Gnomad4 SAS AF: 0.624

Gnomad4 FIN AF: 0.840

Gnomad4 NFE AF: 0.781

Gnomad4 OTH AF: 0.775

Alfa AF: 0.789 Hom.: 11527

Bravo AF: 0.783

Asia WGS AF: 0.718 AC: 2490 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Isolated congenital digital clubbing Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.91
Cadd	Benign	0.31
Dann	Benign	0.095

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: rs2612691; hg19: chr4-175411381;