5-119477487-A-T

Position:

chr5-119477487-A-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.420A>T(p.Lys140Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00458 in 1,612,142 control chromosomes in the GnomAD database, including 180 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 97 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 83 hom. )

Consequence

HSD17B4
NM_000414.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.488

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014483631).

BP6

Variant 5-119477487-A-T is Benign according to our data. Variant chr5-119477487-A-T is described in ClinVar as [Benign]. Clinvar id is 226672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0639 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.420A>T	p.Lys140Asn	missense_variant	7/24	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.420A>T	p.Lys140Asn	missense_variant	7/24	2	NM_000414.4	ENSP00000424940.3		P51659-1

Frequencies

GnomAD3 genomes

AF:

0.0197

AC:

3003

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0658

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00772

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00115

Gnomad OTH

AF:

0.0134

GnomAD3 exomes

AF:

0.00599

AC:

1506

AN:

251368

Hom.:

AF XY:

0.00482

AC XY:

655

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.0649

Gnomad AMR exome

AF:

0.00402

Gnomad ASJ exome

AF:

0.00814

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00209

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00117

Gnomad OTH exome

AF:

0.00456

GnomAD4 exome

AF:

0.00299

AC:

4363

AN:

1459892

Hom.:

Cov.:

AF XY:

0.00281

AC XY:

2043

AN XY:

726438

show subpopulations

Gnomad4 AFR exome

AF:

0.0693

Gnomad4 AMR exome

AF:

0.00416

Gnomad4 ASJ exome

AF:

0.00885

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00203

Gnomad4 FIN exome

AF:

0.000318

Gnomad4 NFE exome

AF:

0.000947

Gnomad4 OTH exome

AF:

0.00545

GnomAD4 genome

AF:

0.0198

AC:

3015

AN:

152250

Hom.:

Cov.:

AF XY:

0.0188

AC XY:

1403

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0659

Gnomad4 AMR

AF:

0.00771

Gnomad4 ASJ

AF:

0.0112

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00115

Gnomad4 OTH

AF:

0.0133

Alfa

AF:

0.00428

Hom.:

Bravo

AF:

0.0224

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0609

AC:

268

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.00720

AC:

874

Asia WGS

AF:

0.00751

AC:

AN:

3478

EpiCase

AF:

0.00120

EpiControl

AF:

0.00190

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 15, 2021	Variant summary: HSD17B4 c.420A>T (p.Lys140Asn) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.006 in 251368 control chromosomes in the gnomAD database, including 46 homozygotes. The observed variant frequency is approximately 2.0 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 benign. To our knowledge, no occurrence of c.420A>T in individuals affected with D-Bifunctional Protein Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Lys165Asn in exon 8 of HSD17B4: This variant is not expected to have clinical si gnificance because it has been identified in 6.1% (268/4404) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs28943589). -

Bifunctional peroxisomal enzyme deficiency

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 24, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Perrault syndrome 1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.69

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

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.085

LIST_S2

Uncertain

0.94

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

MetaRNN

Benign

0.014

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

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.89

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

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.5

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

REVEL

Benign

0.19

Sift

Benign

0.092

T;.;T;.;.;D;.;.;T;.

Sift4G

Benign

0.066

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

Polyphen

0.16

B;.;.;B;.;.;.;B;.;.

Vest4

0.25

MutPred

0.16

Loss of methylation at K140 (P = 0.034);Loss of methylation at K140 (P = 0.034);.;Loss of methylation at K140 (P = 0.034);.;.;Loss of methylation at K140 (P = 0.034);.;.;.;

MVP

0.57

MPC

0.069

ClinPred

0.012

GERP RS

-4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.54

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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