chr4-174522451-T-C

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_000860.6(HPGD):c.1A>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000508 in 1,575,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

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

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

HPGD
NM_000860.6 start_lost

Scores

Clinical Significance

Not reported in ClinVar

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 8 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 12 pathogenic variants. Next in-frame start position is after 122 codons. Genomic position: 174508753. Lost 0.454 part of the original CDS.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HPGD	NM_000860.6	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 7	NP_000851.2
HPGD	NM_001256306.2		c.1A>G	p.Met1?	start_lost	Exon 1 of 5	NP_001243235.1	P15428-5
HPGD	NM_001145816.3		c.1A>G	p.Met1?	start_lost	Exon 1 of 6	NP_001139288.1	P15428-2

Ensembl Transcripts

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

0.000195

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:

0.0000220

AC:

AN:

181474

AF XY:

0.0000101

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000709

Gnomad FIN exome

AF:

0.000120

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000492

AC:

AN:

1423584

Hom.:

Cov.:

AF XY:

0.00000284

AC XY:

AN XY:

704832

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32736

American (AMR)

AF:

0.0000249

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:

0.000122

AC:

AN:

49078

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4142

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1093450

Other (OTH)

AF:

0.00

AC:

AN:

58688

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41574

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000195

AC:

AN:

5126

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ExAC

AF:

0.0000256

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.68

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

0.73

PhyloP100

6.0

PROVEAN

Uncertain

-3.3

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0080

Polyphen

0.99

Vest4

0.81

MutPred

0.98

Loss of sheet (P = 0.1158)

MVP

0.86

ClinPred

0.96

GERP RS

5.0

PromoterAI

-0.020

Neutral

(source)

Varity_R

0.92

gMVP

0.66

Mutation Taster

=1/199

disease causing

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over