rs587777443

Positions:

chr5-119525259-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HSD17B4
NM_000414.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 6.62

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:

HSD17B4 (HGNC:):

HSD17B4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

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	Protein	UniProt
HSD17B4	NM_000414.4 linkuse as main transcript	c.1547T>C	p.Ile516Thr	missense_variant	18/24	ENST00000510025.7	NP_000405.1	P51659-1A0A0S2Z4J1B2R659

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSD17B4	ENST00000510025.7 linkuse as main transcript	c.1547T>C	p.Ile516Thr	missense_variant	18/24	2	NM_000414.4	ENSP00000424940.3		P51659-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

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:

AN:

1459820

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726302

show subpopulations

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:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74306

show subpopulations

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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bifunctional peroxisomal enzyme deficiency

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 11, 2024	Variant summary: HSD17B4 c.1547T>C (p.Ile516Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251020 control chromosomes (gnomAD). c.1547T>C has been reported in the literature in individuals affected with D-Bifunctional Protein Deficiency (e.g. Ferdinandusse_2006, McMillan_2012). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in <10% of normal activity (Tsuchida_2012). The following publications have been ascertained in the context of this evaluation (PMID: 16385454, 22864515, 23181892). ClinVar contains an entry for this variant (Variation ID: 137617). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 12, 2024	- -

Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

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

LIST_S2

Pathogenic

0.99

.;D;D;.;D;D;D;D;D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.42

MutationAssessor

Benign

1.8

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

PrimateAI

Uncertain

0.62

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

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

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