rs11205

Positions:

chr5-119526018-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 12/20 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 4.20

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

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 id is 226667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-119526018-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.442 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.1675A>G	p.Ile559Val	missense_variant	19/24	ENST00000510025.7	NP_000405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSD17B4	ENST00000510025.7 linkuse as main transcript	c.1675A>G	p.Ile559Val	missense_variant	19/24	2	NM_000414.4	ENSP00000424940	P1	P51659-1

Frequencies

GnomAD3 genomes

AF:

0.408

AC:

61907

AN:

151660

Hom.:

12803

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.418

AC:

105063

AN:

251098

Hom.:

22882

AF XY:

0.405

AC XY:

54997

AN XY:

135716

show subpopulations

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 SAS exome

AF:

0.287

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.:

AF XY:

0.397

AC XY:

276028

AN XY:

695156

show subpopulations

Gnomad4 AFR exome

AF:

0.380

Gnomad4 AMR exome

AF:

0.519

Gnomad4 ASJ exome

AF:

0.462

Gnomad4 EAS exome

AF:

0.362

Gnomad4 SAS exome

AF:

0.285

Gnomad4 FIN exome

AF:

0.503

Gnomad4 NFE exome

AF:

0.402

Gnomad4 OTH exome

AF:

0.401

GnomAD4 genome

AF:

0.408

AC:

61948

AN:

151778

Hom.:

12811

Cov.:

AF XY:

0.411

AC XY:

30483

AN XY:

74152

show subpopulations

Gnomad4 AFR

AF:

0.386

Gnomad4 AMR

AF:

0.451

Gnomad4 ASJ

AF:

0.452

Gnomad4 EAS

AF:

0.408

Gnomad4 SAS

AF:

0.303

Gnomad4 FIN

AF:

0.498

Gnomad4 NFE

AF:

0.404

Gnomad4 OTH

AF:

0.397

Alfa

AF:

0.406

Hom.:

19990

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

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 08, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	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). -
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:4

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	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -

Perrault syndrome 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
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

0.071

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.093

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

Eigen

Benign

0.052

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.76

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

MetaRNN

Benign

0.0012

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

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.4

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

MutationTaster

Benign

0.0000014

P;P;P;P;P;P;P

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.48

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

REVEL

Benign

0.29

Sift

Benign

0.28

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

Sift4G

Benign

0.18

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

Polyphen

0.12

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

Vest4

0.16

MPC

0.10

ClinPred

0.015

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.42

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

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