rs150326995

Positions:

chr5-119496624-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000414.4(HSD17B4):c.950C>T(p.Thr317Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000458 in 1,598,012 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 5 hom. )

Consequence

HSD17B4
NM_000414.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:5

Conservation

PhyloP100: 0.624

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:

HSD17B4 (HGNC:):

HSD17B4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01894334).

BP6

Variant 5-119496624-C-T is Benign according to our data. Variant chr5-119496624-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228741.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=6, Benign=2}.

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000481 (696/1445790) while in subpopulation SAS AF= 0.00228 (196/85982). AF 95% confidence interval is 0.00202. There are 5 homozygotes in gnomad4_exome. There are 394 alleles in male gnomad4_exome subpopulation. Median coverage is 27. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSD17B4	NM_000414.4 linkuse as main transcript	c.950C>T	p.Thr317Met	missense_variant	12/24	ENST00000510025.7	NP_000405.1	P51659-1A0A0S2Z4J1B2R659

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSD17B4	ENST00000510025.7 linkuse as main transcript	c.950C>T	p.Thr317Met	missense_variant	12/24	2	NM_000414.4	ENSP00000424940.3		P51659-1

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000461

AC:

116

AN:

251374

Hom.:

AF XY:

0.000655

AC XY:

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00225

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000308

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000481

AC:

696

AN:

1445790

Hom.:

Cov.:

AF XY:

0.000547

AC XY:

394

AN XY:

720384

show subpopulations

Gnomad4 AFR exome

AF:

0.0000604

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00228

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000410

Gnomad4 OTH exome

AF:

0.000401

GnomAD4 genome

AF:

0.000236

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000314

Hom.:

Bravo

AF:

0.000204

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000412

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 18, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 30, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	HSD17B4: BS2 -

Bifunctional peroxisomal enzyme deficiency

Uncertain:1Benign:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 04, 2020	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 03, 2015

The p.Thr342Met variant in HSD17B4 has not been previously reported in individua ls with hearing loss, Perrault syndrome or bi-functional protein deficiency. It has been identified in 0.21% (35/16512) of South Asian chromosomes (with lower f requencies in African, European and Latino chromosomes) by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP ID=rs150326995). Althou gh this variant has been seen in the general population, its frequency is not hi gh enough to rule out a pathogenic role. Computational prediction tools and cons ervation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Thr342Met variant is unc ertain. -

Bifunctional peroxisomal enzyme deficiency;C4551721:Perrault syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Perrault syndrome 1

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

HSD17B4-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 28, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

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

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.21

LIST_S2

Uncertain

0.89

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

M_CAP

Uncertain

0.086

MetaRNN

Benign

0.019

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

MetaSVM

Benign

-0.32

MutationAssessor

Benign

1.8

L;.;L;.;.;.;.;.;.;.;.

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.54

N;N;.;.;N;.;.;.;N;N;.

REVEL

Benign

0.22

Sift

Benign

0.10

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

Sift4G

Benign

0.12

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

Polyphen

0.98

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

Vest4

0.14

MVP

0.88

MPC

0.20

ClinPred

0.047

GERP RS

3.6

Varity_R

0.027

gMVP

0.59

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

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