rs17360144

Variant names:

• chr4-174501850-A-C
• rs17360144
• NM_000860.6:c.422-6226T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0160
• Publications: 2 publications found

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

ACMG classification

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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPGD	NM_000860.6	MANE Select	c.422-6226T>G		intron	N/A	NP_000851.2
	HPGD	NM_001256306.2		c.218-6226T>G		intron	N/A	NP_001243235.1	P15428-5
	HPGD	NM_001145816.3		c.422-6226T>G		intron	N/A	NP_001139288.1	P15428-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPGD	ENST00000296522.11	TSL:1 MANE Select	c.422-6226T>G		intron	N/A	ENSP00000296522.6	P15428-1
	HPGD	ENST00000296521.11	TSL:1	c.422-6226T>G		intron	N/A	ENSP00000296521.7	P15428-2
	HPGD	ENST00000542498.5	TSL:1	c.421+6846T>G		intron	N/A	ENSP00000443644.1	P15428-4

Frequencies

GnomAD3 genomes AF: 0.0593 AC: 9021 AN: 152114 Hom.: 454 Cov.: 33

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.: 33 AF XY: 0.0610 AC XY: 4539 AN XY: 74432

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: 8 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: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0705 AC: 4792 AN: 68004

Other (OTH) AF: 0.0510 AC: 108 AN: 2116

Alfa AF: 0.0648 Hom.: 279

Bravo AF: 0.0610

Asia WGS AF: 0.0290 AC: 99 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.7
DANN	Benign	0.80
PhyloP100		-0.016
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17360144; hg19: chr4-175423001;