4-174501138-G-A

Variant names:

• chr4-174501138-G-A
• rs2612656
• NM_000860.6:c.422-5514C>T

Variant summary

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

The NM_000860.6(HPGD):​c.422-5514C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.786 in 152,126 control chromosomes in the GnomAD database, including 47,196 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 0.79 (47196 hom., cov: 32)
• Consequence: HPGD NM_000860.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.189
• Publications: 8 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, 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.803 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPGD	NM_000860.6	MANE Select	c.422-5514C>T		intron	N/A	NP_000851.2
	HPGD	NM_001256306.2		c.218-5514C>T		intron	N/A	NP_001243235.1
	HPGD	NM_001145816.3		c.422-5514C>T		intron	N/A	NP_001139288.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPGD	ENST00000296522.11	TSL:1 MANE Select	c.422-5514C>T		intron	N/A	ENSP00000296522.6
	HPGD	ENST00000296521.11	TSL:1	c.422-5514C>T		intron	N/A	ENSP00000296521.7
	HPGD	ENST00000542498.5	TSL:1	c.421+7558C>T		intron	N/A	ENSP00000443644.1

Frequencies

GnomAD3 genomes AF: 0.786 AC: 119474 AN: 152008 Hom.: 47150 Cov.: 32

Gnomad AFR AF: 0.810

Gnomad AMI AF: 0.738

Gnomad AMR AF: 0.740

Gnomad ASJ AF: 0.817

Gnomad EAS AF: 0.822

Gnomad SAS AF: 0.622

Gnomad FIN AF: 0.840

Gnomad MID AF: 0.718

Gnomad NFE AF: 0.782

Gnomad OTH AF: 0.783

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

GnomAD4 genome AF: 0.786 AC: 119577 AN: 152126 Hom.: 47196 Cov.: 32 AF XY: 0.785 AC XY: 58369 AN XY: 74356

African (AFR) AF: 0.810 AC: 33608 AN: 41488

American (AMR) AF: 0.740 AC: 11310 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.817 AC: 2837 AN: 3472

East Asian (EAS) AF: 0.822 AC: 4248 AN: 5166

South Asian (SAS) AF: 0.623 AC: 3004 AN: 4820

European-Finnish (FIN) AF: 0.840 AC: 8900 AN: 10592

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.782 AC: 53141 AN: 67980

Other (OTH) AF: 0.778 AC: 1641 AN: 2110

Alfa AF: 0.781 Hom.: 187988

Bravo AF: 0.784

Asia WGS AF: 0.719 AC: 2503 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.5
DANN	Benign	0.72
PhyloP100		-0.19
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: rs2612656; hg19: chr4-175422289;