rs1554068136

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 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 (★★). ClinVar reports functional evidence for this variant: "SCV002600631: At least one publication reports the hydratase activity was abolished by this variant (Tsuchida_2012)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R506C) has been classified as Likely 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
• Publications: 0 publications found

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: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen
• Perrault syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Perrault syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002600631: At least one publication reports the hydratase activity was abolished by this variant (Tsuchida_2012).; SCV003921895: "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); SCV004569604: Experimental studies have shown that this missense change affects HSD17B4 function (PMID: 22864515).
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000414.4
• 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 ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 495866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 554817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000414.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B4	NM_000414.4	MANE Select	c.1517G>A	p.Arg506His	missense	Exon 18 of 24	NP_000405.1	A0A0S2Z4J1
	HSD17B4	NM_001199291.3		c.1592G>A	p.Arg531His	missense	Exon 19 of 25	NP_001186220.1	P51659-2
	HSD17B4	NM_001374497.1		c.1508G>A	p.Arg503His	missense	Exon 18 of 24	NP_001361426.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B4	ENST00000510025.7	TSL:2 MANE Select	c.1517G>A	p.Arg506His	missense	Exon 18 of 24	ENSP00000424940.3	P51659-1
	HSD17B4	ENST00000509514.6	TSL:1	c.1448G>A	p.Arg483His	missense	Exon 18 of 24	ENSP00000426272.2	E7EPL9
	HSD17B4	ENST00000414835.7	TSL:2	c.1592G>A	p.Arg531His	missense	Exon 19 of 25	ENSP00000411960.3	P51659-2

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

African (AFR) AF: 0.0000300 AC: 1 AN: 33384

American (AMR) AF: 0.00 AC: 0 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109996

Other (OTH) AF: 0.00 AC: 0 AN: 60286

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	1	-	Bifunctional peroxisomal enzyme deficiency (4)
1	-	-	Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome (1)
1	-	-	Bifunctional peroxisomal enzyme deficiency;C4551721:Perrault syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		8.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.96		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
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

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