rs28943592

Positions:

chr5-119536489-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000414.4(HSD17B4):c.2060C>T(p.Thr687Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,611,912 control chromosomes in the GnomAD database, including 180 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 13 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 167 hom. )

Consequence

HSD17B4
NM_000414.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.37

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038492382).

BP6

Variant 5-119536489-C-T is Benign according to our data. Variant chr5-119536489-C-T is described in ClinVar as [Benign]. Clinvar id is 226669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSD17B4	NM_000414.4 linkuse as main transcript	c.2060C>T	p.Thr687Ile	missense_variant	23/24	ENST00000510025.7	NP_000405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSD17B4	ENST00000510025.7 linkuse as main transcript	c.2060C>T	p.Thr687Ile	missense_variant	23/24	2	NM_000414.4	ENSP00000424940	P1	P51659-1

Frequencies

GnomAD3 genomes

AF:

0.00365

AC:

555

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00662

Gnomad EAS

AF:

0.0796

Gnomad SAS

AF:

0.00868

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00699

AC:

1756

AN:

251164

Hom.:

AF XY:

0.00682

AC XY:

926

AN XY:

135740

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00595

Gnomad EAS exome

AF:

0.0800

Gnomad SAS exome

AF:

0.00418

Gnomad FIN exome

AF:

0.00157

Gnomad NFE exome

AF:

0.000326

Gnomad OTH exome

AF:

0.00327

GnomAD4 exome

AF:

0.00309

AC:

4517

AN:

1459712

Hom.:

167

Cov.:

AF XY:

0.00321

AC XY:

2332

AN XY:

726222

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.00602

Gnomad4 EAS exome

AF:

0.0850

Gnomad4 SAS exome

AF:

0.00437

Gnomad4 FIN exome

AF:

0.00133

Gnomad4 NFE exome

AF:

0.000222

Gnomad4 OTH exome

AF:

0.00474

GnomAD4 genome

AF:

0.00363

AC:

553

AN:

152200

Hom.:

Cov.:

AF XY:

0.00429

AC XY:

319

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.000578

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00662

Gnomad4 EAS

AF:

0.0794

Gnomad4 SAS

AF:

0.00869

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.000500

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00107

Hom.:

Bravo

AF:

0.00422

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00672

AC:

816

Asia WGS

AF:

0.0380

AC:

133

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Thr712Ile in exon 24 of HSD17B4: This variant is not expected to have clinical s ignificance because it has been identified in 6.5% (13/200) of Han Chinese chrom osomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm. nih.gov/projects/SNP; dbSNP rs28943592). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 01, 2018	Variant summary: HSD17B4 c.2060C>T (p.Thr687Ile) results in a non-conservative amino acid change located in the SCP2 sterol-binding domain of in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0065 in 276846 control chromosomes, predominantly at a frequency of 0.08 within the East Asian subpopulation in the gnomAD database, including 57 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 27.045 fold of the estimated maximal expected allele frequency for a pathogenic variant in HSD17B4 causing D-Bifunctional Protein Deficiency phenotype (0.003), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. Multiple clinical diagnostic laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Bifunctional peroxisomal enzyme deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Bifunctional peroxisomal enzyme deficiency;C4551721:Perrault syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 23, 2022

- -

Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 11, 2018

- -

Perrault syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;.;T;.;.;.;T;.;T;.;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.86

.;D;D;.;D;D;D;D;D;D;D

MetaRNN

Benign

0.0038

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.8

M;.;M;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-4.5

D;D;.;.;D;.;.;.;D;D;.

REVEL

Benign

0.23

Sift

Uncertain

0.012

D;D;.;.;D;.;.;.;D;D;.

Sift4G

Uncertain

0.019

D;D;.;.;D;.;.;.;D;D;.

Polyphen

0.59

P;.;P;.;.;.;P;.;.;D;.

Vest4

0.28

MVP

0.62

MPC

0.17

ClinPred

0.031

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.56

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over