rs587777442

chr5-119456357-C-T

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.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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 4.23

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, 0.964
• PP5: Variant 5-119456357-C-T is Pathogenic according to our data. Variant chr5-119456357-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 137616.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}. Variant chr5-119456357-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD17B4	NM_000414.4	c.101C>T	p.Ala34Val	missense_variant	2/24	ENST00000510025.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD17B4	ENST00000510025.7	c.101C>T	p.Ala34Val	missense_variant	2/24	2	NM_000414.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251446 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135900

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000200 AC: 29 AN: 1453160 Hom.: 0 Cov.: 28 AF XY: 0.0000221 AC XY: 16 AN XY: 723500

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000245

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

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). 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. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2020

- -

Perrault syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 22, 2012

- -

Bifunctional peroxisomal enzyme deficiency;C4551721:Perrault syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Nov 08, 2021

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	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D;.;D;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	0.82	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.56	T
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	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs587777442; hg19: chr5-118792052;