rs577045722

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP3_StrongPP5_Moderate

The NM_001256307.2(HPGD):c.-256A>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000444 in 1,575,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

HPGD
NM_001256307.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 6.01

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

hypertrophic osteoarthropathy, primary, autosomal recessive, 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
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

HPGD links:

ENSG00000251584 (HGNC:58913):

ENSG00000251584 links:

LOC105377548 (HGNC:):

LOC105377548 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 4-174522451-T-A is Pathogenic according to our data. Variant chr4-174522451-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 156026.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256307.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HPGD	NM_000860.6	MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 7	NP_000851.2
HPGD	NM_001256307.2		c.-256A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	NP_001243236.1	P15428-3
HPGD	NM_001256306.2		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 5	NP_001243235.1	P15428-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HPGD	ENST00000296522.11	TSL:1 MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 7	ENSP00000296522.6	P15428-1
HPGD	ENST00000296521.11	TSL:1	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 6	ENSP00000296521.7	P15428-2
HPGD	ENST00000542498.5	TSL:1	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 5	ENSP00000443644.1	P15428-4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000551

AC:

AN:

181474

AF XY:

0.0000101

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000137

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000421

AC:

AN:

1423584

Hom.:

Cov.:

AF XY:

0.00000426

AC XY:

AN XY:

704832

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32736

American (AMR)

AF:

0.00

AC:

AN:

40202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25476

East Asian (EAS)

AF:

0.00

AC:

AN:

37992

South Asian (SAS)

AF:

0.00

AC:

AN:

81820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49078

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4142

European-Non Finnish (NFE)

AF:

0.00000549

AC:

AN:

1093450

Other (OTH)

AF:

0.00

AC:

AN:

58688

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5140

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000171

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypertrophic osteoarthropathy, primary, autosomal recessive, 1 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.48

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.57

PhyloP100

6.0

PROVEAN

Uncertain

-2.4

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

Sift4G

Benign

0.094

Polyphen

0.85

Vest4

0.80

MutPred

0.99

Loss of methylation at K6 (P = 0.0681)

MVP

0.83

ClinPred

0.95

GERP RS

5.0

PromoterAI

-0.20

Neutral

(source)

Varity_R

0.93

gMVP

0.55

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over