rs25640

chr5-119475838-G-Achr5-119475838-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 4P and 20B. PM1 PM5 BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 7.76

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 -16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 id 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 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	UniProt
HSD17B4	NM_000414.4	c.317G>A	p.Arg106His	missense_variant	6/24	ENST00000510025.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD17B4	ENST00000510025.7	c.317G>A	p.Arg106His	missense_variant	6/24	2	NM_000414.4	P1

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58717 AN: 151576 Hom.: 12851 Cov.: 31

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

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.: 30 AF XY: 0.445 AC XY: 319459 AN XY: 717768

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.: 31 AF XY: 0.390 AC XY: 28905 AN XY: 74096

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

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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, 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	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	- -

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 26, 2015	- -

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

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	0.050
Cadd	Pathogenic	26
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	D
MetaRNN	Benign	0.00050	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.99	L;.;.;L;.;.;.;.
MutationTaster	Benign	3.8e-9	P;P;P;P;P
PrimateAI	Uncertain	0.50	T
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	T
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

Other links and lift over

dbSNP: rs25640; hg19: chr5-118811533; COSMIC: COSV56333773; COSMIC: COSV56333773;