dbSNP rs17360144: HPGD:c.422-6226T>G (chr4-174501850-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000860.6(HPGD):c.422-6226T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0593 in 152,232 control chromosomes in the GnomAD database, including 456 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.059 ( 456 hom., cov: 33)

Consequence

HPGD
NM_000860.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0160

Publications

2 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPGD	NM_000860.6 link	c.422-6226T>G		intron_variant	Intron 4 of 6	ENST00000296522.11	NP_000851.2	P15428-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPGD	ENST00000296522.11 link	c.422-6226T>G		intron_variant	Intron 4 of 6	1	NM_000860.6	ENSP00000296522.6		P15428-1

Frequencies

GnomAD3 genomes

AF:

0.0593

AC:

9021

AN:

152114

Hom.:

454

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0145

Gnomad AMI

AF:

0.0603

Gnomad AMR

AF:

0.134

Gnomad ASJ

AF:

0.0338

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.0810

Gnomad FIN

AF:

0.0850

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0705

Gnomad OTH

AF:

0.0516

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0593

AC:

9027

AN:

152232

Hom.:

456

Cov.:

AF XY:

0.0610

AC XY:

4539

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0144

AC:

599

AN:

41568

American (AMR)

AF:

0.134

AC:

2048

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0338

AC:

117

AN:

3466

East Asian (EAS)

AF:

0.00154

AC:

AN:

5188

South Asian (SAS)

AF:

0.0804

AC:

388

AN:

4824

European-Finnish (FIN)

AF:

0.0850

AC:

900

AN:

10590

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0705

AC:

4792

AN:

68004

Other (OTH)

AF:

0.0510

AC:

108

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

424

848

1272

1696

2120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

106

212

318

424

530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0648

Hom.:

279

Bravo

AF:

0.0610

Asia WGS

AF:

0.0290

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

4.7

(source)

DANN

Benign

0.80

PhyloP100

-0.016

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over