rs25640

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 4P and 20B. PM1PM5BP4_StrongBP6_Very_StrongBA1

The NM_000414.4(HSD17B4):c.317G>A(p.Arg106His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.442 in 1,592,192 control chromosomes in the GnomAD database, including 160,587 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R106P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.39 ( 12859 hom., cov: 31)

Exomes 𝑓: 0.45 ( 147728 hom. )

Consequence

HSD17B4
NM_000414.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 7.76

Publications

65 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 -16 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000414.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-119475838-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 7657.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=5.040467E-4).

BP6

Variant 5-119475838-G-A is Benign according to our data. Variant chr5-119475838-G-A is described in ClinVar as Benign. ClinVar VariationId is 198079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B4	NM_000414.4 link	c.317G>A	p.Arg106His	missense_variant	Exon 6 of 24	ENST00000510025.7	NP_000405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B4	ENST00000510025.7 link	c.317G>A	p.Arg106His	missense_variant	Exon 6 of 24	2	NM_000414.4	ENSP00000424940.3

Frequencies

GnomAD3 genomes

AF:

0.387

AC:

58717

AN:

151576

Hom.:

12851

Cov.:

show subpopulations

Gnomad AFR

AF:

0.174

Gnomad AMI

AF:

0.671

Gnomad AMR

AF:

0.467

Gnomad ASJ

AF:

0.495

Gnomad EAS

AF:

0.499

Gnomad SAS

AF:

0.366

Gnomad FIN

AF:

0.509

Gnomad MID

AF:

0.398

Gnomad NFE

AF:

0.463

Gnomad OTH

AF:

0.417

GnomAD2 exomes

AF:

0.451

AC:

113143

AN:

250942

AF XY:

0.446

show subpopulations

Gnomad AFR exome

AF:

0.164

Gnomad AMR exome

AF:

0.559

Gnomad ASJ exome

AF:

0.504

Gnomad EAS exome

AF:

0.521

Gnomad FIN exome

AF:

0.508

Gnomad NFE exome

AF:

0.458

Gnomad OTH exome

AF:

0.467

GnomAD4 exome

AF:

0.447

AC:

644525

AN:

1440498

Hom.:

147728

Cov.:

AF XY:

0.445

AC XY:

319459

AN XY:

717768

show subpopulations

African (AFR)

AF:

0.159

AC:

5303

AN:

33248

American (AMR)

AF:

0.552

AC:

24637

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.504

AC:

13082

AN:

25952

East Asian (EAS)

AF:

0.463

AC:

18275

AN:

39480

South Asian (SAS)

AF:

0.354

AC:

30403

AN:

85798

European-Finnish (FIN)

AF:

0.508

AC:

27085

AN:

53290

Middle Eastern (MID)

AF:

0.418

AC:

2377

AN:

5688

European-Non Finnish (NFE)

AF:

0.455

AC:

497649

AN:

1092700

Other (OTH)

AF:

0.431

AC:

25714

AN:

59708

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

15346

30692

46039

61385

76731

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14670

29340

44010

58680

73350

<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:

0.387

AC:

58748

AN:

151694

Hom.:

12859

Cov.:

AF XY:

0.390

AC XY:

28905

AN XY:

74096

show subpopulations

African (AFR)

AF:

0.174

AC:

7217

AN:

41366

American (AMR)

AF:

0.468

AC:

7137

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.495

AC:

1718

AN:

3470

East Asian (EAS)

AF:

0.499

AC:

2574

AN:

5154

South Asian (SAS)

AF:

0.366

AC:

1762

AN:

4810

European-Finnish (FIN)

AF:

0.509

AC:

5341

AN:

10498

Middle Eastern (MID)

AF:

0.394

AC:

115

AN:

292

European-Non Finnish (NFE)

AF:

0.463

AC:

31400

AN:

67838

Other (OTH)

AF:

0.415

AC:

875

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1675

3349

5024

6698

8373

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

574

1148

1722

2296

2870

<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:

0.445

Hom.:

66822

Bravo

AF:

0.380

TwinsUK

AF:

0.468

AC:

1736

ALSPAC

AF:

0.470

AC:

1810

ESP6500AA

AF:

0.176

AC:

776

ESP6500EA

AF:

0.460

AC:

3954

ExAC

AF:

0.440

AC:

53356

Asia WGS

AF:

0.427

AC:

1472

AN:

3458

EpiCase

AF:

0.454

EpiControl

AF:

0.455

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 16, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 31, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Arg131His in exon 7 of HSD17B4: This variant is not expected to have clinical si gnificance because it has been identified in 46% (3954/8596) of European America n chromosomes and 18% (776/4404) of African American chromosomes by the NHLBI Ex ome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs25640). -

Bifunctional peroxisomal enzyme deficiency

Benign:3

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

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided

Benign:2

Oct 26, 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

- -

Apr 27, 2017

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

Benign

0.15

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;.;.;D;.;.;.;D

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

.;D;D;D;.;D;D;D

MetaRNN

Benign

0.00050

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

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.99

L;.;.;L;.;.;.;.

PhyloP100

7.8

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.4

D;.;D;.;.;D;.;.

REVEL

Uncertain

0.58

Sift

Uncertain

0.020

D;.;D;.;.;D;.;.

Sift4G

Uncertain

0.012

D;.;D;.;.;D;.;.

Polyphen

0.98

D;.;.;D;.;.;.;D

Vest4

0.21

MPC

0.19

ClinPred

0.024

GERP RS

5.7

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.40

gMVP

0.84

Mutation Taster

=254/46

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.12

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