5-119526018-A-G

Variant names:

• chr5-119526018-A-G
• rs11205
• NM_000414.4:c.1675A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000414.4(HSD17B4):​c.1675A>G​(p.Ile559Val) variant causes a missense change. The variant allele was found at a frequency of 0.402 in 1,540,756 control chromosomes in the GnomAD database, including 126,774 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (12811 hom., cov: 32)
  • Exomes 𝑓: 0.40 (113963 hom.)
• Consequence: HSD17B4 NM_000414.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 4.20
• Publications: 55 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 14 uncertain in NM_000414.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0011920929).
• BP6: Variant 5-119526018-A-G is Benign according to our data. Variant chr5-119526018-A-G is described in ClinVar as Benign. ClinVar VariationId is 226667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.442 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000414.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B4	NM_000414.4	MANE Select	c.1675A>G	p.Ile559Val	missense	Exon 19 of 24	NP_000405.1
	HSD17B4	NM_001199291.3		c.1750A>G	p.Ile584Val	missense	Exon 20 of 25	NP_001186220.1
	HSD17B4	NM_001374497.1		c.1666A>G	p.Ile556Val	missense	Exon 19 of 24	NP_001361426.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B4	ENST00000510025.7	TSL:2 MANE Select	c.1675A>G	p.Ile559Val	missense	Exon 19 of 24	ENSP00000424940.3
	HSD17B4	ENST00000509514.6	TSL:1	c.1606A>G	p.Ile536Val	missense	Exon 19 of 24	ENSP00000426272.2
	HSD17B4	ENST00000414835.7	TSL:2	c.1750A>G	p.Ile584Val	missense	Exon 20 of 25	ENSP00000411960.3

Frequencies

GnomAD3 genomes AF: 0.408 AC: 61907 AN: 151660 Hom.: 12803 Cov.: 32

Gnomad AFR AF: 0.386

Gnomad AMI AF: 0.440

Gnomad AMR AF: 0.451

Gnomad ASJ AF: 0.452

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.498

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.404

Gnomad OTH AF: 0.398

GnomAD2 exomes AF: 0.418 AC: 105063 AN: 251098 AF XY: 0.405

Gnomad AFR exome AF: 0.387

Gnomad AMR exome AF: 0.527

Gnomad ASJ exome AF: 0.455

Gnomad EAS exome AF: 0.414

Gnomad FIN exome AF: 0.504

Gnomad NFE exome AF: 0.407

Gnomad OTH exome AF: 0.411

GnomAD4 exome AF: 0.402 AC: 557757 AN: 1388978 Hom.: 113963 Cov.: 24 AF XY: 0.397 AC XY: 276028 AN XY: 695156

African (AFR) AF: 0.380 AC: 12168 AN: 32006

American (AMR) AF: 0.519 AC: 23128 AN: 44534

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 11863 AN: 25688

East Asian (EAS) AF: 0.362 AC: 14224 AN: 39276

South Asian (SAS) AF: 0.285 AC: 24164 AN: 84844

European-Finnish (FIN) AF: 0.503 AC: 26833 AN: 53366

Middle Eastern (MID) AF: 0.371 AC: 2080 AN: 5604

European-Non Finnish (NFE) AF: 0.402 AC: 420103 AN: 1045798

Other (OTH) AF: 0.401 AC: 23194 AN: 57862

GnomAD4 genome AF: 0.408 AC: 61948 AN: 151778 Hom.: 12811 Cov.: 32 AF XY: 0.411 AC XY: 30483 AN XY: 74152

African (AFR) AF: 0.386 AC: 15982 AN: 41432

American (AMR) AF: 0.451 AC: 6871 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 1566 AN: 3466

East Asian (EAS) AF: 0.408 AC: 2109 AN: 5170

South Asian (SAS) AF: 0.303 AC: 1463 AN: 4824

European-Finnish (FIN) AF: 0.498 AC: 5215 AN: 10468

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.404 AC: 27397 AN: 67880

Other (OTH) AF: 0.397 AC: 837 AN: 2106

Alfa AF: 0.405 Hom.: 28042

Bravo AF: 0.411

TwinsUK AF: 0.421 AC: 1560

ALSPAC AF: 0.407 AC: 1569

ESP6500AA AF: 0.395 AC: 1741

ESP6500EA AF: 0.409 AC: 3518

ExAC AF: 0.410 AC: 49838

Asia WGS AF: 0.381 AC: 1319 AN: 3472

EpiCase AF: 0.400

EpiControl AF: 0.398

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bifunctional peroxisomal enzyme deficiency Benign:4

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 13, 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.

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:4

Aug 08, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ile584Val in exon 20 of HSD17B4: This variant is not expected to have clinical s ignificance because it has been identified in 40.9% (3518/8600) of European Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs11205).

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

not provided Benign:2

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 23, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Perrault syndrome 1 Benign:2

Jan 13, 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

Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.093	T
Eigen	Benign	0.052
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.29
Sift	Benign	0.28	T
Sift4G	Benign	0.18	T
Polyphen		0.12	B
Vest4		0.16
MPC		0.10
ClinPred		0.015	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.42
Mutation Taster		=96/4	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: rs11205; hg19: chr5-118861713; COSMIC: COSV56333537; COSMIC: COSV56333537;