rs137853096

chr5-119452621-G-Achr5-119452621-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000414.4(HSD17B4):c.46G>A(p.Gly16Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000328 in 1,613,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G16G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: HSD17B4 NM_000414.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:25 U:1 O:1
• Conservation: PhyloP100: 4.86

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 5-119452621-G-A is Pathogenic according to our data. Variant chr5-119452621-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 7655.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=16, Likely_pathogenic=3, Uncertain_significance=1, not_provided=1}. Variant chr5-119452621-G-A is described in Lovd as [Pathogenic]. Variant chr5-119452621-G-A is described in Lovd as [Likely_pathogenic]. Variant chr5-119452621-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD17B4	NM_000414.4	c.46G>A	p.Gly16Ser	missense_variant	1/24	ENST00000510025.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD17B4	ENST00000510025.7	c.46G>A	p.Gly16Ser	missense_variant	1/24	2	NM_000414.4	P1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000200 AC: 50 AN: 250088 Hom.: 0 AF XY: 0.000229 AC XY: 31 AN XY: 135192

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000400

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000344 AC: 503 AN: 1461646 Hom.: 0 Cov.: 34 AF XY: 0.000336 AC XY: 244 AN XY: 727144

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000436

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74330

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000372 Hom.: 0

Bravo AF: 0.000170

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.000545

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:25 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Bifunctional peroxisomal enzyme deficiency Pathogenic:10 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 02, 2016	Variant summary: The c.46G>A (p.Gly16Ser) in HSD17B4 gene is a missense change that involves a conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant of interest is located within the dehydrogenase domain and mutations were proven to lead to inactivation of the 3-hydroxyacyl-CoA dehydrogenase component. The variant is present in the large control population dataset of ExAC at a low frequency 0.0002 (27/121004 chrs tested), which does not exceed the maximal expected frequency of a pathogenic allele (0.0029) in this gene. The variant has been reported in multiple affected individuals in homozygous and compound heterozygous state from and was proven to segregate with the disease reputable databases/clinical laboratories classified this variant as Pathogenic. The c.46G>A is widely accepted to be one of the most common pathogenic variants to cause D-BPD. Taken together, the variant was classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 26, 2019	NM_000414.3(HSD17B4):c.46G>A(G16S) is classified as likely pathogenic in the context of D-bifunctional protein deficiency. Sources cited for classification include the following: PMID 16385454, 9482850, 10419023 and 10497229. Classification of NM_000414.3(HSD17B4):c.46G>A(G16S) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 04, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.020%). While this variant results in missense change, protein truncation variants are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 10419023 , 10497229 , 9482850). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.95). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 25967389 , 9482850). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jun 10, 2022	PS3, PM3_Strong, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 26, 2022	- -
Likely pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	HSD17B4 c.46G>A is predicted to result in a single amino acid change from glycine to serine. It is the most common pathogenic variant associated with DBP deficiency and has been reported in over 30 individuals with DBP deficiency (PMID:9482850; 16385454; 25967389; 26970254). -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	Sep 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 03, 2023	Identified as compund heterozygous with NM_000414.4:c.53G>T. Criteria applied: PM3_VSTR,PM2_SUP,PP3 -

not provided Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 19, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 27, 2019	DNA sequence analysis of the HSD17B4 gene demonstrated a sequence change, c.46G>A, in exon 1 that results in an amino acid change, p.Gly16Ser. This sequence change has been reported in multiple individuals with D-bifunctional protein deficiency in both homozygous and compound heterozygous state with another variant (PMID: 25967389, PMID: 9482850, PMID:16385454). It has also been identified in a patient with Perrault syndrome who presented with bilateral progressive sensorineural hearing loss, premature ovarian insufficiency and progressive cerebellar ataxia (PMID: 26970254). This sequence change has been described in the gnomAD database with a low population frequency of 0.038% in non-Finnish European subpopulation; however, it has not been observed in homozygous state in any individuals (dbSNP rs137853096). The p.Gly16Ser change affects a highly conserved amino acid residue located in a domain of the HSD17B4 protein that is known to be functional. This sequence change is located in an important loop of the Rossman fold which forms the binding site for the essential cofactor NAD+ and is predicted to alter the binding site. Expression studies in yeast showed that this mutant causes loss of the 3-hydroxyacyl-CoA dehydrogenase activity, an essential component of d-bifunctional protein (PMID: 9482850). The p.Gly16Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). These collective evidences indicate that this sequence change is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	HSD17B4: PM3:Very Strong, PM2, PP3, PP4, PS3:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2023	Published functional studies demonstrate variant inactivates the 3-hydroxyacyl-CoA dehydrogenase component of the D-bifunctional protein (van Grunsven et al., 1998); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23308274, 11165012, 25967389, 10343282, 9482850, 26970254, 27290639, 27650058, 31980526, 34906502, 34426522, 34493867) -

Perrault syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 26, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as PATHOGENIC. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine (exon 1). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (57 heterozygotes, 0 homozygote). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in-silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (NAD nucleotide binding region, NCBI). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously described as pathogenic in multiple patients with D-bifunctional protein deficiency and Perrault syndrome (ClinVar, PMID: 9482850, 25967389, 26970254). (P) 0903 - Low evidence for segregation with disease. The variant segregated with disease in two families with D-bifunctional protein deficiency (PMID: 9482850, 25967389). (P) 1001 - Strong functional evidence supporting abnormal protein function. Expression studies showed that this variant causes the loss of 3-hydroxyacylCoA dehydrogenase activity and biochemical analysis concluded the blockage in dehydrogenation of VLCFA too (PMID: 9482850, 25967389). (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	May 07, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3. -

HSD17B4-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 23, 2024	The HSD17B4 c.46G>A variant is predicted to result in the amino acid substitution p.Gly16Ser. This variant is known to be causative for D-bifunctional protein deficiency and Perrault syndrome, with functional experiments showing this results in inactive dehydrogenase enzymatic activity (van Grunsven et al. 1998. PubMed ID: 9482850; Demain et al. 2016. PubMed ID: 26970254; Pronicka et al. 2016. PubMed ID: 27290639). This variant is reported in 0.038% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 16, 2018	The HSD17B4 c.46G>A (p.Gly16Ser) missense variant has been reported in at least five studies and has been identified in at least 29 probands with peroxisomal bifunctional enzyme deficiency, including in 26 individuals in a homozygous state and in three individuals in a compound heterozygous state (van Grunsven et al. 1998; van Grunsven et al. 1999; Ferdinandusse et al. 2006; Konkoľová et al. 2015). The variant was also identified in a compound heterozygous state with a missense variant in one individual with Perrault syndrome (Demain et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000391 in the European (non-Finnish) population of the Genome Aggregation Database. The p.Gly16Ser variant is located at a conserved residue in a loop affecting the binding site of the dehydrogenase region of the protein. Functional studies in yeast expressing the variant and wild type protein showed loss of 3-hydroxyacyl-CoA dehydrogenase activity, but did not affect the enoyl-CoA hydratase activity (van Grunsven et al. 1998). Based on the collective evidence, the p.Gly16Ser variant is classified as pathogenic for HSD17B4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 16 of the HSD17B4 protein (p.Gly16Ser). This variant is present in population databases (rs137853096, gnomAD 0.04%). This missense change has been observed in individuals with D-bifunctional protein deficiency (PMID: 9482850, 16385454, 25967389). ClinVar contains an entry for this variant (Variation ID: 7655). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HSD17B4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects HSD17B4 function (PMID: 9482850, 10419023, 10497229). For these reasons, this variant has been classified as Pathogenic. -

Perrault syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

-

The most common pathogenic variant causing D-bifunctional protein deficiency. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.;.;D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.1	H;.;H;H;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.3	D;.;D;.;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;.;D;.;.
Sift4G	Pathogenic	0.0	D;.;D;.;.
Polyphen		1.0	D;.;.;D;.
Vest4		0.94
MVP		0.96
ClinPred		0.81	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.98

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: rs137853096; hg19: chr5-118788316;