4-174503021-G-A

Variant names:

• chr4-174503021-G-A
• rs7349744
• NM_000860.6:c.421+5675C>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.421+5675C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 152,104 control chromosomes in the GnomAD database, including 5,309 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 0.24 (5309 hom., cov: 32)
• Consequence: HPGD NM_000860.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.787
• Publications: 6 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.301 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.421+5675C>T		intron	N/A	NP_000851.2
	HPGD	NM_001256306.2		c.218-7397C>T		intron	N/A	NP_001243235.1
	HPGD	NM_001145816.3		c.421+5675C>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.421+5675C>T		intron	N/A	ENSP00000296522.6
	HPGD	ENST00000296521.11	TSL:1	c.421+5675C>T		intron	N/A	ENSP00000296521.7
	HPGD	ENST00000542498.5	TSL:1	c.421+5675C>T		intron	N/A	ENSP00000443644.1

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37104 AN: 151986 Hom.: 5304 Cov.: 32

Gnomad AFR AF: 0.0983

Gnomad AMI AF: 0.263

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.292

Gnomad FIN AF: 0.356

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.270

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

GnomAD4 genome AF: 0.244 AC: 37121 AN: 152104 Hom.: 5309 Cov.: 32 AF XY: 0.249 AC XY: 18540 AN XY: 74334

African (AFR) AF: 0.0983 AC: 4080 AN: 41506

American (AMR) AF: 0.228 AC: 3493 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 1265 AN: 3472

East Asian (EAS) AF: 0.299 AC: 1542 AN: 5150

South Asian (SAS) AF: 0.293 AC: 1412 AN: 4814

European-Finnish (FIN) AF: 0.356 AC: 3758 AN: 10566

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.304 AC: 20679 AN: 67994

Other (OTH) AF: 0.269 AC: 568 AN: 2108

Alfa AF: 0.285 Hom.: 10020

Bravo AF: 0.230

Asia WGS AF: 0.303 AC: 1057 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.33
DANN	Benign	0.72
PhyloP100		-0.79
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: rs7349744; hg19: chr4-175424172;