rs1554068136

Variant names:

• chr5-119525229-G-A
• rs1554068136
• NM_000414.4:c.1517G>A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000414.4(HSD17B4):​c.1517G>A​(p.Arg506His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,350 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. R506C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: HSD17B4 NM_000414.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• Conservation: PhyloP100: 8.26

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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-119525228-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 5-119525229-G-A is Pathogenic according to our data. Variant chr5-119525229-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 554817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-119525229-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B4	NM_000414.4	c.1517G>A	p.Arg506His	missense_variant	Exon 18 of 24	ENST00000510025.7	NP_000405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B4	ENST00000510025.7	c.1517G>A	p.Arg506His	missense_variant	Exon 18 of 24	2	NM_000414.4	ENSP00000424940.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459350 Hom.: 0 Cov.: 28 AF XY: 0.00000413 AC XY: 3 AN XY: 726088

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bifunctional peroxisomal enzyme deficiency Pathogenic:3 Uncertain:1

Nov 13, 2017

Counsyl

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with D-bifunctional protein deficiency (MIM#261515) and Perrault syndrome 1 (MIM#233400). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (4 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated MaoC-like domain (DECIPHER). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. The p.(Arg506Cys) variant has been reported in three individuals with DBP deficiency (PMID: 16385454), and as likely pathogenic/pathogenic in ClinVar. (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. It has been reported as homozygous in an individual with D-bifunctional protein deficiency (PMID: 16385454). The variant has also been reported as a VUS in ClinVar however no further evidence was provided. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1006 - Clinically accredited laboratory assay shows abnormal function of product not specific to the gene. VLCFA assay showed abnormal result in this individual (personal communication). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000414.3:c.31dupG, p.(Val11Glyfs*30)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Aug 24, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 21, 2022

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HSD17B4 c.1517G>A (p.Arg506His) results in a non-conservative amino acid change located in the MaoC-like dehydratase domain (IPR002539) of 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 250870 control chromosomes (gnomAD). c.1517G>A (p.R506H) has been reported in the literature in at least one homozygous individual affected with D-Bifunctional Protein Deficiency (Ferdinandusse_2006). In addition, another variant (R506C) at the same residue was found in three homozygous patients affected with DBP II (Ferdinandusse_2006) and this variant has been classified as DV in our lab, suggesting this residue is clinical and fuctional important. These data indicate that the variant may be associated with disease. At least one publication reports the hydratase activity was abolished by this variant (Tsuchida_2012). One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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

Mar 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Sep 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 554817). 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) performed at Invitae indicates that this missense variant is expected to disrupt HSD17B4 protein function. Experimental studies have shown that this missense change affects HSD17B4 function (PMID: 22864515). This variant disrupts the p.Arg506 amino acid residue in HSD17B4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16385454, 25967389). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This missense change has been observed in individual(s) with D-bifunctional protein deficiency (PMID: 16385454). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 506 of the HSD17B4 protein (p.Arg506His). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T;.;T;.;.;.;T;.;T;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	.;D;D;.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.8	H;.;H;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.8	D;D;.;.;D;.;.;.;D;D;.
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;D;.;.;D;.;.;.;D;D;.
Sift4G	Pathogenic	0.0	D;D;.;.;D;.;.;.;D;D;.
Polyphen		1.0	D;.;D;.;.;.;D;.;.;D;.
Vest4		0.92
MutPred		0.96		Loss of catalytic residue at R506 (P = 0.1266);.;Loss of catalytic residue at R506 (P = 0.1266);.;.;Loss of catalytic residue at R506 (P = 0.1266);.;.;.;.;.;
MVP		0.96
MPC		0.41
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.99
gMVP		0.87

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: rs1554068136; hg19: chr5-118860924; COSMIC: COSV56334524; COSMIC: COSV56334524;