5-119509176-A-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000414.4(HSD17B4):c.1369A>T(p.Asn457Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,604,088 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N457D) has been classified as Pathogenic.

Frequency

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

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

HSD17B4
NM_000414.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 7.77

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-119509176-A-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.949

PP5

Variant 5-119509176-A-T is Pathogenic according to our data. Variant chr5-119509176-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-119509176-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B4	NM_000414.4 link	c.1369A>T	p.Asn457Tyr	missense_variant	Exon 16 of 24	ENST00000510025.7	NP_000405.1	P51659-1A0A0S2Z4J1B2R659

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B4	ENST00000510025.7 link	c.1369A>T	p.Asn457Tyr	missense_variant	Exon 16 of 24	2	NM_000414.4	ENSP00000424940.3		P51659-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152152

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:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251434

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000158

AC:

AN:

1451936

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

723004

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

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:

0.0000127

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

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:

0.00

Gnomad4 OTH

AF:

0.000479

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bifunctional peroxisomal enzyme deficiency

Pathogenic:8

Jul 22, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 02, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS4 moderate, PM2, PM3, PP3 -

Dec 07, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 14561219, 18332091). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 0.47). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001076782). 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: 12234283, 25964309). Different missense changes at the same codon (p.Arg365Gln, p.Arg365Leu, p.Arg365Pro) have been reported to be associated with SLC3A1-related disorder (ClinVar ID: VCV000562304 /PMID: 10464673, 14991253, 16138908). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

May 06, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as homozygous._x000D_ Criteria applied: PM3_VSTR, PS3_SUP, PM2_SUP, PP3 -

Mar 11, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 09, 2019

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000414.3(HSD17B4):c.1369A>T(N457Y) is classified as likely pathogenic in the context of D-bifunctional protein deficiency. Sources cited for classification include the following: PMID 12562856, 16385454 and 10400999. Classification of NM_000414.3(HSD17B4):c.1369A>T(N457Y) 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. -

Oct 17, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HSD17B4 c.1369A>T (p.Asn457Tyr) 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 allele was found at a frequency of 1.6e-05 in 251434 control chromosomes. c.1369A>T has been reported in the literature in multiple individuals affected with D-Bifunctional Protein Deficiency (vanGrunsven_1999, Nascimento_2015). These data indicate that the variant is very likely to be associated with disease. Two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (vanGrunsven_1999, Tsuchida_2012). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Bifunctional peroxisomal enzyme deficiency;C4551721:Perrault syndrome 1

Pathogenic:2

Dec 15, 2015

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jun 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Pathogenic:1

Nov 28, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HSD17B4 c.1444A>T; p.Asn482Tyr variant (rs137853097), also known as p.Asn457Tyr, is reported in the literature in individuals affected with D-bifunctional protein deficiency, both in the homozygous state and in trans to a pathogenic variant (Ferdinandusse 2006, Nascimento 2015, van Grunsven 1999). Biochemical assays of hydratase function indicate that the p.Asn482Tyr variant has severely impaired enzymatic activity (Tsuchida 2012, van Grunsven 1999). Additionally, another variant at this codon (p.Asn482Asp) has been reported in an individual with D-bifunctional protein deficiency (Ferdinandusse 2006) and was demonstrated to have negligible hydratase activity (Tsuchida 2012). The p.Asn482Tyr variant is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 7656) and it is found on only four chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. The asparagine at codon 482 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. References: Ferdinandusse S et al. Mutational spectrum of D-bifunctional protein deficiency and structure-based genotype-phenotype analysis. Am J Hum Genet. 2006 Jan;78(1):112-24. Nascimento J et al. D-bifunctional protein deficiency: a cause of neonatal onset seizures and hypotonia. Pediatr Neurol. 2015 May;52(5):539-43. Tsuchida S et al. Hydratase activities of green fluorescent protein tagged human multifunctional enzyme type 2 hydratase domain and its variants. J Oleo Sci. 2012;61(8):443-50. van Grunsven EG et al. Enoyl-CoA hydratase deficiency: identification of a new type of D-bifunctional protein deficiency. Hum Mol Genet. 1999 Aug;8(8):1509-16. -

Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome

Pathogenic:1

Nov 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 457 of the HSD17B4 protein (p.Asn457Tyr). This variant is present in population databases (rs137853097, gnomAD 0.006%). This missense change has been observed in individuals with D-bifunctional protein deficiency (PMID: 10400999, 16385454, 23181892, 25882080). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7656). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt HSD17B4 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HSD17B4 function (PMID: 10400999, 22864515). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Mar 20, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate this variant disrupts domain folding and reduces hydratase activity to less than 10% of wild type (van Grunsven et al., 1999; Tsuchida et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10400999, 22864515, 25882080, 25967389, 16385454, 31589614) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.80

D;.;D;.;.;.;T;.;T;.;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

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

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.95

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

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

3.8

H;.;H;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-6.1

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

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.0020

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

Polyphen

1.0

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

Vest4

0.91

MVP

0.97

MPC

0.41

ClinPred

0.98

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.90

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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