5-119452501-C-G

Position:

• chr5-119452501-C-G

Variant summary

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

The NM_000414.4(HSD17B4):​c.-75C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.473 in 1,610,302 control chromosomes in the GnomAD database, including 183,344 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (15155 hom., cov: 33)
  • Exomes 𝑓: 0.48 (168189 hom.)
• Consequence: HSD17B4 NM_000414.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0680

Genes affected

HSD17B4 (HGNC:5213): (hydroxysteroid 17-beta dehydrogenase 4) The protein encoded by this gene is a bifunctional enzyme that is involved in the peroxisomal beta-oxidation pathway for fatty acids. It also acts as a catalyst for the formation of 3-ketoacyl-CoA intermediates from both straight-chain and 2-methyl-branched-chain fatty acids. Defects in this gene that affect the peroxisomal fatty acid beta-oxidation activity are a cause of D-bifunctional protein deficiency (DBPD). An apparent pseudogene of this gene is present on chromosome 8. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 5-119452501-C-G is Benign according to our data. Variant chr5-119452501-C-G is described in ClinVar as [Benign]. Clinvar id is 350457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.486 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSD17B4	NM_000414.4	c.-75C>G		5_prime_UTR_variant	1/24	ENST00000510025.7	NP_000405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSD17B4	ENST00000510025.7	c.-75C>G		5_prime_UTR_variant	1/24	2	NM_000414.4	ENSP00000424940	P1

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65737 AN: 151990 Hom.: 15142 Cov.: 33

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.675

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.548

Gnomad EAS AF: 0.499

Gnomad SAS AF: 0.383

Gnomad FIN AF: 0.548

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.464

GnomAD4 exome AF: 0.477 AC: 695856 AN: 1458194 Hom.: 168189 Cov.: 33 AF XY: 0.475 AC XY: 344384 AN XY: 725544

Gnomad4 AFR exome AF: 0.266

Gnomad4 AMR exome AF: 0.571

Gnomad4 ASJ exome AF: 0.557

Gnomad4 EAS exome AF: 0.463

Gnomad4 SAS exome AF: 0.374

Gnomad4 FIN exome AF: 0.557

Gnomad4 NFE exome AF: 0.483

Gnomad4 OTH exome AF: 0.464

GnomAD4 genome AF: 0.432 AC: 65786 AN: 152108 Hom.: 15155 Cov.: 33 AF XY: 0.434 AC XY: 32290 AN XY: 74354

Gnomad4 AFR AF: 0.273

Gnomad4 AMR AF: 0.495

Gnomad4 ASJ AF: 0.548

Gnomad4 EAS AF: 0.499

Gnomad4 SAS AF: 0.383

Gnomad4 FIN AF: 0.548

Gnomad4 NFE AF: 0.487

Gnomad4 OTH AF: 0.461

Alfa AF: 0.331 Hom.: 924

Bravo AF: 0.428

Asia WGS AF: 0.456 AC: 1580 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bifunctional peroxisomal enzyme deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
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. -

Perrault syndrome 1 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 24, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.7
DANN	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs26180; hg19: chr5-118788196; COSMIC: COSV56333370; COSMIC: COSV56333370;