rs9312555

Variant names:

• chr4-174490802-A-G
• rs9312555
• NM_000860.6:c.*1154T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000860.6(HPGD):​c.*1154T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 152,246 control chromosomes in the GnomAD database, including 2,861 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2859 hom., cov: 32)
  • Exomes 𝑓: 0.12 (2 hom.)
• Consequence: HPGD NM_000860.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.98
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 4-174490802-A-G is Benign according to our data. Variant chr4-174490802-A-G is described in ClinVar as Benign. ClinVar VariationId is 348180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.498 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.*1154T>C		3_prime_UTR	Exon 7 of 7	NP_000851.2
	HPGD	NM_001256306.2		c.*1154T>C		3_prime_UTR	Exon 5 of 5	NP_001243235.1	P15428-5
	HPGD	NM_001145816.3		c.*1254T>C		3_prime_UTR	Exon 6 of 6	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.*1154T>C		3_prime_UTR	Exon 7 of 7	ENSP00000296522.6	P15428-1
	HPGD	ENST00000542498.5	TSL:1	c.*1282T>C		3_prime_UTR	Exon 5 of 5	ENSP00000443644.1	P15428-4
	HPGD	ENST00000541923.5	TSL:2	c.*1154T>C		3_prime_UTR	Exon 6 of 6	ENSP00000438017.1	P15428-3

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26365 AN: 151992 Hom.: 2855 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.514

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.175

GnomAD4 exome AF: 0.116 AC: 16 AN: 138 Hom.: 2 Cov.: 0 AF XY: 0.132 AC XY: 10 AN XY: 76

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.116 AC: 16 AN: 138

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.173 AC: 26376 AN: 152108 Hom.: 2859 Cov.: 32 AF XY: 0.177 AC XY: 13187 AN XY: 74358

African (AFR) AF: 0.133 AC: 5506 AN: 41512

American (AMR) AF: 0.281 AC: 4284 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 564 AN: 3466

East Asian (EAS) AF: 0.515 AC: 2657 AN: 5164

South Asian (SAS) AF: 0.170 AC: 822 AN: 4824

European-Finnish (FIN) AF: 0.160 AC: 1697 AN: 10592

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.151 AC: 10266 AN: 67968

Other (OTH) AF: 0.173 AC: 366 AN: 2112

Alfa AF: 0.163 Hom.: 3750

Bravo AF: 0.183

Asia WGS AF: 0.286 AC: 992 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hypertrophic osteoarthropathy, primary, autosomal recessive, 1 (1)
-	-	1	Isolated congenital digital clubbing (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.077
DANN	Benign	0.36
PhyloP100		-2.0
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: rs9312555; hg19: chr4-175411953;