dbSNP rs9312555: HPGD:c.*1154T>C (chr4-174490802-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.98

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
HPGD	NM_000860.6 link	c.*1154T>C		3_prime_UTR_variant	Exon 7 of 7	ENST00000296522.11	NP_000851.2	P15428-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
HPGD	ENST00000296522 link	c.*1154T>C	3_prime_UTR_variant	Exon 7 of 7	1	NM_000860.6	ENSP00000296522.6	P15428-1
HPGD	ENST00000542498 link	c.*1282T>C	3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000443644.1	P15428-4
HPGD	ENST00000541923 link	c.*1154T>C	3_prime_UTR_variant	Exon 6 of 6	2		ENSP00000438017.1	P15428-3

Frequencies

GnomAD3 genomes

AF:

0.173

AC:

26365

AN:

151992

Hom.:

2855

Cov.:

show subpopulations

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:

AN:

138

Hom.:

Cov.:

AF XY:

0.132

AC XY:

AN XY:

show subpopulations

Gnomad4 EAS exome

AF:

0.116

GnomAD4 genome

AF:

0.173

AC:

26376

AN:

152108

Hom.:

2859

Cov.:

AF XY:

0.177

AC XY:

13187

AN XY:

74358

show subpopulations

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

LINK: link

Submissions by phenotype

Hypertrophic osteoarthropathy, primary, autosomal recessive, 1

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Isolated congenital digital clubbing

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over