4-174491326-C-T

Position:

• chr4-174491326-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000296522.11(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 ENST00000296522.11 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.158

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPGD	NM_000860.6	c.*630G>A		3_prime_UTR_variant	7/7	ENST00000296522.11	NP_000851.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPGD	ENST00000296522.11	c.*630G>A		3_prime_UTR_variant	7/7	1	NM_000860.6	ENSP00000296522	P1
HPGD	ENST00000542498.5	c.*758G>A		3_prime_UTR_variant	5/5	1		ENSP00000443644
HPGD	ENST00000541923.5	c.*630G>A		3_prime_UTR_variant	6/6	2		ENSP00000438017
HPGD	ENST00000510835.5	c.*1193G>A		3_prime_UTR_variant, NMD_transcript_variant	6/6	5		ENSP00000427699

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.333

Gnomad4 ASJ exome AF: 0.833

Gnomad4 EAS exome AF: 0.580

Gnomad4 FIN exome AF: 0.667

Gnomad4 NFE exome AF: 0.371

Gnomad4 OTH exome AF: 0.667

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

Gnomad4 AFR AF: 0.328

Gnomad4 AMR AF: 0.402

Gnomad4 ASJ AF: 0.634

Gnomad4 EAS AF: 0.303

Gnomad4 SAS AF: 0.442

Gnomad4 FIN AF: 0.646

Gnomad4 NFE AF: 0.587

Gnomad4 OTH AF: 0.509

Alfa AF: 0.563 Hom.: 49600

Bravo AF: 0.464

Asia WGS AF: 0.399 AC: 1390 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic osteoarthropathy, primary, autosomal recessive, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Isolated congenital digital clubbing Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.2
DANN	Benign	0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs8752; hg19: chr4-175412477; COSMIC: COSV56662547; COSMIC: COSV56662547;