5-119456357-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_000414.4(HSD17B4):c.101C>T(p.Ala34Val) variant causes a missense change. The variant allele was found at a frequency of 0.00002 in 1,453,160 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. A34A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

HSD17B4
NM_000414.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 4.23

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

d-bifunctional protein deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
Perrault syndrome
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Perrault syndrome 1
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia

HSD17B4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.964

PP5

Variant 5-119456357-C-T is Pathogenic according to our data. Variant chr5-119456357-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 137616. Variant chr5-119456357-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 137616. Variant chr5-119456357-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 137616. Variant chr5-119456357-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 137616. Variant chr5-119456357-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 137616. Variant chr5-119456357-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 137616. Variant chr5-119456357-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 137616. Variant chr5-119456357-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 137616. Variant chr5-119456357-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 137616. Variant chr5-119456357-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 137616. Variant chr5-119456357-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 137616. Variant chr5-119456357-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 137616. Variant chr5-119456357-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 137616. Variant chr5-119456357-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 137616.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B4	NM_000414.4 link	c.101C>T	p.Ala34Val	missense_variant	Exon 2 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.101C>T	p.Ala34Val	missense_variant	Exon 2 of 24	2	NM_000414.4	ENSP00000424940.3		P51659-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000795

AC:

AN:

251446

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000200

AC:

AN:

1453160

Hom.:

Cov.:

AF XY:

0.0000221

AC XY:

AN XY:

723500

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33290

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26092

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86074

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000245

AC:

AN:

1104122

Other (OTH)

AF:

0.00

AC:

AN:

60044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Bifunctional peroxisomal enzyme deficiency

Pathogenic:1

Mar 26, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome

Pathogenic:1

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 34 of the HSD17B4 protein (p.Ala34Val). This variant is present in population databases (rs587777442, gnomAD 0.006%). This missense change has been observed in individual(s) with D-bifunctional protein deficiency (PMID: 16385454, 23181892, 34719423). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 137616). 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) has been performed 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. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Nov 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Perrault syndrome 1

Pathogenic:1

Nov 22, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Bifunctional peroxisomal enzyme deficiency;C4551721:Perrault syndrome 1

Uncertain:1

Nov 08, 2021

Myriad Genetics, Inc.

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NM_000414.3(HSD17B4):c.101C>T(A34V) is a missense variant classified as a variant of uncertain significance in the context of D-bifunctional protein deficiency. A34V has been observed in cases with relevant disease (PMID: 23181892, 16385454). Functional assessments of this variant are not available in the literature. A34V has been observed in population frequency databases (gnomAD: EAS 0.01%). In summary, there is insufficient evidence to classify NM_000414.3(HSD17B4):c.101C>T(A34V) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

D;.;D;.

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.99

.;D;D;D

M_CAP

Benign

0.083

MetaRNN

Pathogenic

0.96

D;D;D;D

MetaSVM

Pathogenic

0.82

PhyloP100

4.2

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.4

D;.;.;.

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0010

D;.;.;.

Sift4G

Uncertain

0.0020

D;.;.;.

Polyphen

1.0

D;.;D;.

Vest4

0.86

MutPred

0.88

Gain of loop (P = 0);Gain of loop (P = 0);Gain of loop (P = 0);Gain of loop (P = 0);

MVP

0.96

ClinPred

0.78

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.94

Mutation Taster

=23/77

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over