rs25640

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5BP4_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

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 links:

HSD17B4 (HGNC:):

HSD17B4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-119475838-G-C is described in Lovd as [Pathogenic].

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 id is 198079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-119475838-G-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
HSD17B4	NM_000414.4 linkuse as main transcript	c.317G>A	p.Arg106His	missense_variant	6/24	ENST00000510025.7	NP_000405.1	P51659-1A0A0S2Z4J1B2R659

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSD17B4	ENST00000510025.7 linkuse as main transcript	c.317G>A	p.Arg106His	missense_variant	6/24	2	NM_000414.4	ENSP00000424940.3		P51659-1

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

GnomAD3 exomes

AF:

0.451

AC:

113143

AN:

250942

Hom.:

26942

AF XY:

0.446

AC XY:

60545

AN XY:

135622

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 SAS exome

AF:

0.351

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

Gnomad4 AFR exome

AF:

0.159

Gnomad4 AMR exome

AF:

0.552

Gnomad4 ASJ exome

AF:

0.504

Gnomad4 EAS exome

AF:

0.463

Gnomad4 SAS exome

AF:

0.354

Gnomad4 FIN exome

AF:

0.508

Gnomad4 NFE exome

AF:

0.455

Gnomad4 OTH exome

AF:

0.431

GnomAD4 genome

AF:

0.387

AC:

58748

AN:

151694

Hom.:

12859

Cov.:

AF XY:

0.390

AC XY:

28905

AN XY:

74096

show subpopulations

Gnomad4 AFR

AF:

0.174

Gnomad4 AMR

AF:

0.468

Gnomad4 ASJ

AF:

0.495

Gnomad4 EAS

AF:

0.499

Gnomad4 SAS

AF:

0.366

Gnomad4 FIN

AF:

0.509

Gnomad4 NFE

AF:

0.463

Gnomad4 OTH

AF:

0.415

Alfa

AF:

0.453

Hom.:

37528

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

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 16, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 31, 2014	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). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 26, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Perrault syndrome 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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

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;.;.;.;.

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

Splicing

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over