chr5-119452501-C-G

Variant names:

• chr5-119452501-C-G
• rs26180
• NM_000414.4:c.-75C>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 10 publications found

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]

HSD17B4 Gene-Disease associations (from GenCC):

• d-bifunctional protein deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• Perrault syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Perrault syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
HSD17B4	NM_000414.4	c.-75C>G		5_prime_UTR_variant	Exon 1 of 24	ENST00000510025.7	NP_000405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B4	ENST00000510025.7	c.-75C>G		5_prime_UTR_variant	Exon 1 of 24	2	NM_000414.4	ENSP00000424940.3

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

African (AFR) AF: 0.266 AC: 8899 AN: 33416

American (AMR) AF: 0.571 AC: 25449 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.557 AC: 14545 AN: 26106

East Asian (EAS) AF: 0.463 AC: 18371 AN: 39676

South Asian (SAS) AF: 0.374 AC: 32177 AN: 86132

European-Finnish (FIN) AF: 0.557 AC: 29589 AN: 53154

Middle Eastern (MID) AF: 0.481 AC: 2235 AN: 4646

European-Non Finnish (NFE) AF: 0.483 AC: 536672 AN: 1110292

Other (OTH) AF: 0.464 AC: 27919 AN: 60180

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

African (AFR) AF: 0.273 AC: 11322 AN: 41514

American (AMR) AF: 0.495 AC: 7565 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.548 AC: 1901 AN: 3472

East Asian (EAS) AF: 0.499 AC: 2563 AN: 5136

South Asian (SAS) AF: 0.383 AC: 1848 AN: 4824

European-Finnish (FIN) AF: 0.548 AC: 5791 AN: 10576

Middle Eastern (MID) AF: 0.438 AC: 128 AN: 292

European-Non Finnish (NFE) AF: 0.487 AC: 33080 AN: 67986

Other (OTH) AF: 0.461 AC: 974 AN: 2114

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

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.7
DANN	Benign	0.55
PhyloP100		0.068
PromoterAI		0.058	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs26180; hg19: chr5-118788196; COSMIC: COSV56333370; COSMIC: COSV56333370;