rs11539471

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000414.4(HSD17B4):c.1531T>C(p.Trp511Arg) variant causes a missense change. The variant allele was found at a frequency of 0.085 in 1,610,606 control chromosomes in the GnomAD database, including 7,951 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 2174 hom., cov: 32)

Exomes 𝑓: 0.080 ( 5777 hom. )

Consequence

HSD17B4
NM_000414.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 6.62

Publications

31 publications found

Variant links:

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

HSD17B4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000414.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0032287538).

BP6

Variant 5-119525243-T-C is Benign according to our data. Variant chr5-119525243-T-C is described in ClinVar as Benign. ClinVar VariationId is 226665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B4	NM_000414.4 link	c.1531T>C	p.Trp511Arg	missense_variant	Exon 18 of 24	ENST00000510025.7	NP_000405.1	P51659-1A0A0S2Z4J1B2R659

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B4	ENST00000510025.7 link	c.1531T>C	p.Trp511Arg	missense_variant	Exon 18 of 24	2	NM_000414.4	ENSP00000424940.3		P51659-1

Frequencies

GnomAD3 genomes

AF:

0.134

AC:

20412

AN:

151958

Hom.:

2176

Cov.:

show subpopulations

Gnomad AFR

AF:

0.295

Gnomad AMI

AF:

0.0429

Gnomad AMR

AF:

0.0887

Gnomad ASJ

AF:

0.0873

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.0364

Gnomad FIN

AF:

0.0849

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.0763

Gnomad OTH

AF:

0.0993

GnomAD2 exomes

AF:

0.0861

AC:

21602

AN:

250924

AF XY:

0.0788

show subpopulations

Gnomad AFR exome

AF:

0.301

Gnomad AMR exome

AF:

0.106

Gnomad ASJ exome

AF:

0.0861

Gnomad EAS exome

AF:

0.00130

Gnomad FIN exome

AF:

0.0869

Gnomad NFE exome

AF:

0.0764

Gnomad OTH exome

AF:

0.0730

GnomAD4 exome

AF:

0.0798

AC:

116424

AN:

1458530

Hom.:

5777

Cov.:

AF XY:

0.0778

AC XY:

56463

AN XY:

725704

show subpopulations

African (AFR)

AF:

0.298

AC:

9942

AN:

33326

American (AMR)

AF:

0.104

AC:

4655

AN:

44622

Ashkenazi Jewish (ASJ)

AF:

0.0848

AC:

2213

AN:

26082

East Asian (EAS)

AF:

0.00310

AC:

123

AN:

39660

South Asian (SAS)

AF:

0.0384

AC:

3314

AN:

86212

European-Finnish (FIN)

AF:

0.0878

AC:

4688

AN:

53378

Middle Eastern (MID)

AF:

0.0689

AC:

396

AN:

5750

European-Non Finnish (NFE)

AF:

0.0775

AC:

85975

AN:

1109262

Other (OTH)

AF:

0.0850

AC:

5118

AN:

60238

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

4548

9095

13643

18190

22738

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3282

6564

9846

13128

16410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.134

AC:

20424

AN:

152076

Hom.:

2174

Cov.:

AF XY:

0.131

AC XY:

9743

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.295

AC:

12226

AN:

41454

American (AMR)

AF:

0.0885

AC:

1350

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.0873

AC:

303

AN:

3470

East Asian (EAS)

AF:

0.00231

AC:

AN:

5194

South Asian (SAS)

AF:

0.0365

AC:

176

AN:

4826

European-Finnish (FIN)

AF:

0.0849

AC:

900

AN:

10600

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0763

AC:

5186

AN:

67976

Other (OTH)

AF:

0.0983

AC:

207

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

820

1641

2461

3282

4102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

200

400

600

800

1000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0966

Hom.:

2416

Bravo

AF:

0.145

TwinsUK

AF:

0.0817

AC:

303

ALSPAC

AF:

0.0716

AC:

276

ESP6500AA

AF:

0.301

AC:

1324

ESP6500EA

AF:

0.0772

AC:

664

ExAC

AF:

0.0889

AC:

10788

Asia WGS

AF:

0.0390

AC:

136

AN:

3478

EpiCase

AF:

0.0781

EpiControl

AF:

0.0715

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Trp536Arg in exon 19 of HSD17B4: This variant is not expected to have clinical s ignificance because it has been identified in 30.1% (1324/4404) of African Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs11539471). -

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. -

Bifunctional peroxisomal enzyme deficiency

Benign:3

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

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. -

not provided

Benign:2

Oct 23, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Perrault syndrome 1

Benign:2

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

T;.;T;.;.;.;T;.;T;.;.

Eigen

Benign

-0.12

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.62

.;T;T;.;T;T;T;T;T;T;T

MetaRNN

Benign

0.0032

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.47

N;.;N;.;.;.;.;.;.;.;.

PhyloP100

6.6

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-2.5

D;D;.;.;D;.;.;.;D;N;.

REVEL

Benign

0.28

Sift

Benign

0.39

T;T;.;.;T;.;.;.;T;T;.

Sift4G

Benign

0.39

T;T;.;.;T;.;.;.;T;T;.

Polyphen

0.010

B;.;B;.;.;.;B;.;.;B;.

Vest4

0.78

MutPred

0.45

Gain of disorder (P = 0.0069);.;Gain of disorder (P = 0.0069);.;.;Gain of disorder (P = 0.0069);.;.;.;.;.;

MPC

0.11

ClinPred

0.017

GERP RS

5.6

Varity_R

0.76

gMVP

0.93

Mutation Taster

=25/75

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over