rs11539471

Variant names:

• chr5-119525243-T-C
• rs11539471
• NM_000414.4:c.1531T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001199291.3(HSD17B4):​c.1606T>C​(p.Trp536Arg) variant causes a missense change. The variant allele was found at a frequency of 0.085 in 1,610,606 control chromosomes in the GnomAD database, including 7,951 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (2174 hom., cov: 32)
  • Exomes 𝑓: 0.080 (5777 hom.)
• Consequence: HSD17B4 NM_001199291.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 6.62
• Publications: 31 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: 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

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001199291.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0032287538).
• BP6: Variant 5-119525243-T-C is Benign according to our data. Variant chr5-119525243-T-C is described in ClinVar as Benign. ClinVar VariationId is 226665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199291.3. 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.1531T>C	p.Trp511Arg	missense	Exon 18 of 24	NP_000405.1
	HSD17B4	NM_001199291.3		c.1606T>C	p.Trp536Arg	missense	Exon 19 of 25	NP_001186220.1
	HSD17B4	NM_001374497.1		c.1522T>C	p.Trp508Arg	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.1531T>C	p.Trp511Arg	missense	Exon 18 of 24	ENSP00000424940.3
	HSD17B4	ENST00000509514.6	TSL:1	c.1462T>C	p.Trp488Arg	missense	Exon 18 of 24	ENSP00000426272.2
	HSD17B4	ENST00000414835.7	TSL:2	c.1606T>C	p.Trp536Arg	missense	Exon 19 of 25	ENSP00000411960.3

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20412 AN: 151958 Hom.: 2176 Cov.: 32

Gnomad AFR AF: 0.295

Gnomad AMI AF: 0.0429

Gnomad AMR AF: 0.0887

Gnomad ASJ AF: 0.0873

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0364

Gnomad FIN AF: 0.0849

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0763

Gnomad OTH AF: 0.0993

GnomAD2 exomes AF: 0.0861 AC: 21602 AN: 250924 AF XY: 0.0788

Gnomad AFR exome AF: 0.301

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.0861

Gnomad EAS exome AF: 0.00130

Gnomad FIN exome AF: 0.0869

Gnomad NFE exome AF: 0.0764

Gnomad OTH exome AF: 0.0730

GnomAD4 exome AF: 0.0798 AC: 116424 AN: 1458530 Hom.: 5777 Cov.: 29 AF XY: 0.0778 AC XY: 56463 AN XY: 725704

African (AFR) AF: 0.298 AC: 9942 AN: 33326

American (AMR) AF: 0.104 AC: 4655 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.0848 AC: 2213 AN: 26082

East Asian (EAS) AF: 0.00310 AC: 123 AN: 39660

South Asian (SAS) AF: 0.0384 AC: 3314 AN: 86212

European-Finnish (FIN) AF: 0.0878 AC: 4688 AN: 53378

Middle Eastern (MID) AF: 0.0689 AC: 396 AN: 5750

European-Non Finnish (NFE) AF: 0.0775 AC: 85975 AN: 1109262

Other (OTH) AF: 0.0850 AC: 5118 AN: 60238

GnomAD4 genome AF: 0.134 AC: 20424 AN: 152076 Hom.: 2174 Cov.: 32 AF XY: 0.131 AC XY: 9743 AN XY: 74348

African (AFR) AF: 0.295 AC: 12226 AN: 41454

American (AMR) AF: 0.0885 AC: 1350 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.0873 AC: 303 AN: 3470

East Asian (EAS) AF: 0.00231 AC: 12 AN: 5194

South Asian (SAS) AF: 0.0365 AC: 176 AN: 4826

European-Finnish (FIN) AF: 0.0849 AC: 900 AN: 10600

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0763 AC: 5186 AN: 67976

Other (OTH) AF: 0.0983 AC: 207 AN: 2106

Alfa AF: 0.0966 Hom.: 2416

Bravo AF: 0.145

TwinsUK AF: 0.0817 AC: 303

ALSPAC AF: 0.0716 AC: 276

ESP6500AA AF: 0.301 AC: 1324

ESP6500EA AF: 0.0772 AC: 664

ExAC AF: 0.0889 AC: 10788

Asia WGS AF: 0.0390 AC: 136 AN: 3478

EpiCase AF: 0.0781

EpiControl AF: 0.0715

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Bifunctional peroxisomal enzyme deficiency (3)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	2	Perrault syndrome 1 (2)
-	-	1	Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.47	N
PhyloP100		6.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.28
Sift	Benign	0.39	T
Sift4G	Benign	0.39	T
Polyphen		0.010	B
Vest4		0.78
MutPred		0.45		Gain of disorder (P = 0.0069)
MPC		0.11
ClinPred		0.017	T
GERP RS		5.6
Varity_R		0.76
gMVP		0.93
Mutation Taster		=25/75	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11539471; hg19: chr5-118860938; COSMIC: COSV56338044; COSMIC: COSV56338044;