rs28943590

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_000414.4(HSD17B4):c.1280C>T(p.Ala427Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,581,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. A427A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000063 ( 0 hom. )

Consequence

HSD17B4
NM_000414.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 2.38

Publications

1 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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01742968).

BP6

Variant 5-119506836-C-T is Benign according to our data. Variant chr5-119506836-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 439793.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000629 (90/1429908) while in subpopulation AMR AF = 0.00193 (86/44618). AF 95% confidence interval is 0.0016. There are 0 homozygotes in GnomAdExome4. There are 31 alleles in the male GnomAdExome4 subpopulation. Median coverage is 24. This position passed quality control check.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HSD17B4	NM_000414.4	MANE Select	c.1280C>T	p.Ala427Val	missense	Exon 15 of 24	NP_000405.1
HSD17B4	NM_001199291.3		c.1355C>T	p.Ala452Val	missense	Exon 16 of 25	NP_001186220.1
HSD17B4	NM_001374497.1		c.1271C>T	p.Ala424Val	missense	Exon 15 of 24	NP_001361426.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HSD17B4	ENST00000510025.7	TSL:2 MANE Select	c.1280C>T	p.Ala427Val	missense	Exon 15 of 24	ENSP00000424940.3
HSD17B4	ENST00000509514.6	TSL:1	c.1280C>T	p.Ala427Val	missense	Exon 15 of 24	ENSP00000426272.2
HSD17B4	ENST00000414835.7	TSL:2	c.1355C>T	p.Ala452Val	missense	Exon 16 of 25	ENSP00000411960.3

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000327

AC:

AN:

250798

AF XY:

0.000199

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00238

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000629

AC:

AN:

1429908

Hom.:

Cov.:

AF XY:

0.0000434

AC XY:

AN XY:

713512

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32894

American (AMR)

AF:

0.00193

AC:

AN:

44618

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25858

East Asian (EAS)

AF:

0.00

AC:

AN:

39354

South Asian (SAS)

AF:

0.00

AC:

AN:

85458

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53218

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5388

European-Non Finnish (NFE)

AF:

0.00000277

AC:

AN:

1084008

Other (OTH)

AF:

0.0000169

AC:

AN:

59112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.434

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

AF:

0.0000592

AC:

AN:

152070

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41400

American (AMR)

AF:

0.000524

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.531

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000151

ExAC

AF:

0.000272

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome (1)

HSD17B4-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Benign

0.0094

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.044

MetaRNN

Benign

0.017

MetaSVM

Benign

-0.41

MutationAssessor

Uncertain

2.3

PhyloP100

2.4

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.34

Sift

Benign

0.24

Sift4G

Benign

0.41

Polyphen

0.22

Vest4

0.43

MutPred

0.19

Gain of catalytic residue at A427 (P = 0.1137)

MVP

0.77

MPC

0.080

ClinPred

0.17

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.23

gMVP

0.65

Mutation Taster

=47/53

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over