4-174491326-C-T

Variant names:

• chr4-174491326-C-T
• rs8752
• NM_000860.6:c.*630G>A

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.*630G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.488 in 152,340 control chromosomes in the GnomAD database, including 19,491 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (19359 hom., cov: 31)
  • Exomes 𝑓: 0.61 (132 hom.)
• Consequence: HPGD NM_000860.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.158
• Publications: 25 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=-0.81).
• BP6: Variant 4-174491326-C-T is Benign according to our data. Variant chr4-174491326-C-T is described in ClinVar as Benign. ClinVar VariationId is 348188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.582 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.*630G>A		3_prime_UTR	Exon 7 of 7	NP_000851.2
	HPGD	NM_001256306.2		c.*630G>A		3_prime_UTR	Exon 5 of 5	NP_001243235.1	P15428-5
	HPGD	NM_001145816.3		c.*730G>A		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.*630G>A		3_prime_UTR	Exon 7 of 7	ENSP00000296522.6	P15428-1
	HPGD	ENST00000542498.5	TSL:1	c.*758G>A		3_prime_UTR	Exon 5 of 5	ENSP00000443644.1	P15428-4
	HPGD	ENST00000541923.5	TSL:2	c.*630G>A		3_prime_UTR	Exon 6 of 6	ENSP00000438017.1	P15428-3

Frequencies

GnomAD3 genomes AF: 0.487 AC: 73813 AN: 151526 Hom.: 19347 Cov.: 31

Gnomad AFR AF: 0.328

Gnomad AMI AF: 0.549

Gnomad AMR AF: 0.403

Gnomad ASJ AF: 0.634

Gnomad EAS AF: 0.303

Gnomad SAS AF: 0.441

Gnomad FIN AF: 0.646

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.587

Gnomad OTH AF: 0.512

GnomAD4 exome AF: 0.606 AC: 422 AN: 696 Hom.: 132 Cov.: 0 AF XY: 0.610 AC XY: 239 AN XY: 392

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.333 AC: 6 AN: 18

Ashkenazi Jewish (ASJ) AF: 0.833 AC: 5 AN: 6

East Asian (EAS) AF: 0.580 AC: 94 AN: 162

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.667 AC: 287 AN: 430

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.371 AC: 26 AN: 70

Other (OTH) AF: 0.667 AC: 4 AN: 6

GnomAD4 genome AF: 0.487 AC: 73861 AN: 151644 Hom.: 19359 Cov.: 31 AF XY: 0.486 AC XY: 35988 AN XY: 74094

African (AFR) AF: 0.328 AC: 13567 AN: 41404

American (AMR) AF: 0.402 AC: 6129 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.634 AC: 2199 AN: 3468

East Asian (EAS) AF: 0.303 AC: 1560 AN: 5148

South Asian (SAS) AF: 0.442 AC: 2125 AN: 4808

European-Finnish (FIN) AF: 0.646 AC: 6794 AN: 10522

Middle Eastern (MID) AF: 0.483 AC: 141 AN: 292

European-Non Finnish (NFE) AF: 0.587 AC: 39772 AN: 67754

Other (OTH) AF: 0.509 AC: 1073 AN: 2108

Alfa AF: 0.551 Hom.: 98810

Bravo AF: 0.464

Asia WGS AF: 0.399 AC: 1390 AN: 3474

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	-0.81
CADD	Benign	7.2
DANN	Benign	0.60
PhyloP100		0.16
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: rs8752; hg19: chr4-175412477; COSMIC: COSV56662547; COSMIC: COSV56662547;