rs587777443

chr5-119525259-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000414.4(HSD17B4):c.1547T>C(p.Ile516Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,611,928 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. I516I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HSD17B4 NM_000414.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• 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 Pathogenic. 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 1 benign, 3 uncertain in NM_000414.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 5-119525259-T-C is Pathogenic according to our data. Variant chr5-119525259-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 137617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-119525259-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD17B4	NM_000414.4	c.1547T>C	p.Ile516Thr	missense_variant	18/24	ENST00000510025.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD17B4	ENST00000510025.7	c.1547T>C	p.Ile516Thr	missense_variant	18/24	2	NM_000414.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459820 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726302

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74306

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bifunctional peroxisomal enzyme deficiency Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 06, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 30, 2023

Experimental studies have shown that this missense change affects HSD17B4 function (PMID: 22864515). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HSD17B4 protein function. ClinVar contains an entry for this variant (Variation ID: 137617). This missense change has been observed in individuals with clinical features of HSD17B4-related disorders (PMID: 16385454, 23181892, 24108619, 28708278). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 516 of the HSD17B4 protein (p.Ile516Thr). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Nov 15, 2021

- -

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 18, 2018

The p.Ile541Thr variant (also referred to as Ile516Thr) in HSD17B4 has been repo rted in 3 individuals with D-bifunctional protein deficiency and segregated with the disease in 1 affected (Ferdinandusse 2006. McMillan 2012). It was absent fr om large population studies. All reported individuals were compound heterozygote s with different missense alleles, including likely pathogenic variants. The p.I le541Thr variant has been reported in ClinVar (Variation ID: 137617). In vitro f unctional data suggest that this mutation impacts protein dimerization, resultin g in reduced function (Ferdinandusse 2006, Tsuchida 2016); however, these types of assays may not accurately represent biological function. Computational predic tion tools and conservation analysis suggest that the p.Ile541Thr variant may i mpact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully es tablish its clinical significance, the p.Ile541Thr variant is likely pathogenic. ACMG/AMP Criteria applied: PM2; PM3; PP3; PS3_Supporting -

Perrault syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 22, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.;T;.;.;.;T;.;T;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	1.8	L;.;L;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.6	D;D;.;.;D;.;.;.;D;D;.
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D;D;.;.;D;.;.;.;D;D;.
Sift4G	Uncertain	0.0020	D;D;.;.;D;.;.;.;D;D;.
Polyphen		0.99	D;.;D;.;.;.;D;.;.;D;.
Vest4		0.87
MutPred		0.91		Loss of stability (P = 0.0213);.;Loss of stability (P = 0.0213);.;.;Loss of stability (P = 0.0213);.;.;.;.;.;
MVP		0.93
MPC		0.42
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.88
gMVP		0.85

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: rs587777443; hg19: chr5-118860954;