rs11539471

chr5-119525243-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 6.62

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 5 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 id 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/exons	MANE	UniProt
HSD17B4	NM_000414.4	c.1531T>C	p.Trp511Arg	missense_variant	18/24	ENST00000510025.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD17B4	ENST00000510025.7	c.1531T>C	p.Trp511Arg	missense_variant	18/24	2	NM_000414.4	P1

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20412 AN: 151958 Hom.: 2176 Cov.: 32

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

GnomAD3 exomes AF: 0.0861 AC: 21602 AN: 250924 Hom.: 1434 AF XY: 0.0788 AC XY: 10680 AN XY: 135608

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 SAS exome AF: 0.0379

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.: 29 AF XY: 0.0778 AC XY: 56463 AN XY: 725704

Gnomad4 AFR exome AF: 0.298

Gnomad4 AMR exome AF: 0.104

Gnomad4 ASJ exome AF: 0.0848

Gnomad4 EAS exome AF: 0.00310

Gnomad4 SAS exome AF: 0.0384

Gnomad4 FIN exome AF: 0.0878

Gnomad4 NFE exome AF: 0.0775

Gnomad4 OTH exome AF: 0.0850

GnomAD4 genome AF: 0.134 AC: 20424 AN: 152076 Hom.: 2174 Cov.: 32 AF XY: 0.131 AC XY: 9743 AN XY: 74348

Gnomad4 AFR AF: 0.295

Gnomad4 AMR AF: 0.0885

Gnomad4 ASJ AF: 0.0873

Gnomad4 EAS AF: 0.00231

Gnomad4 SAS AF: 0.0365

Gnomad4 FIN AF: 0.0849

Gnomad4 NFE AF: 0.0763

Gnomad4 OTH AF: 0.0983

Alfa AF: 0.0857 Hom.: 1288

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

Submissions by phenotype

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	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. -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	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). -
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. -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 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	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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	22
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	D
MetaRNN	Benign	0.0032	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.47	N;.;N;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.0000014	P;P;P;P;P;P;P
PrimateAI	Uncertain	0.71	T
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	T
GERP RS		5.6
Varity_R		0.76
gMVP		0.93

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

Other links and lift over

dbSNP: rs11539471; hg19: chr5-118860938; COSMIC: COSV56338044; COSMIC: COSV56338044;