5-119477487-A-T

Variant names:

• chr5-119477487-A-T
• rs28943589
• NM_000414.4:c.420A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 14/21 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.488
• Publications: 12 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 -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 VariationId 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B4	NM_000414.4	MANE Select	c.420A>T	p.Lys140Asn	missense	Exon 7 of 24	NP_000405.1
	HSD17B4	NM_001199291.3		c.495A>T	p.Lys165Asn	missense	Exon 8 of 25	NP_001186220.1
	HSD17B4	NM_001374497.1		c.420A>T	p.Lys140Asn	missense	Exon 7 of 24	NP_001361426.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B4	ENST00000510025.7	TSL:2 MANE Select	c.420A>T	p.Lys140Asn	missense	Exon 7 of 24	ENSP00000424940.3
	HSD17B4	ENST00000509514.6	TSL:1	c.420A>T	p.Lys140Asn	missense	Exon 7 of 24	ENSP00000426272.2
	HSD17B4	ENST00000414835.7	TSL:2	c.495A>T	p.Lys165Asn	missense	Exon 8 of 25	ENSP00000411960.3

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 3003 AN: 152132 Hom.: 98 Cov.: 32

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

GnomAD2 exomes AF: 0.00599 AC: 1506 AN: 251368 AF XY: 0.00482

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 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.: 83 Cov.: 29 AF XY: 0.00281 AC XY: 2043 AN XY: 726438

African (AFR) AF: 0.0693 AC: 2312 AN: 33380

American (AMR) AF: 0.00416 AC: 186 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00885 AC: 231 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00203 AC: 175 AN: 86228

European-Finnish (FIN) AF: 0.000318 AC: 17 AN: 53412

Middle Eastern (MID) AF: 0.0108 AC: 62 AN: 5760

European-Non Finnish (NFE) AF: 0.000947 AC: 1051 AN: 1110336

Other (OTH) AF: 0.00545 AC: 329 AN: 60312

GnomAD4 genome AF: 0.0198 AC: 3015 AN: 152250 Hom.: 97 Cov.: 32 AF XY: 0.0188 AC XY: 1403 AN XY: 74448

African (AFR) AF: 0.0659 AC: 2737 AN: 41516

American (AMR) AF: 0.00771 AC: 118 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4826

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00115 AC: 78 AN: 68028

Other (OTH) AF: 0.0133 AC: 28 AN: 2112

Alfa AF: 0.00428 Hom.: 9

Bravo AF: 0.0224

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0609 AC: 268

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00720 AC: 874

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00190

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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).

Sep 18, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 15, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Bifunctional peroxisomal enzyme deficiency Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 24, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Perrault syndrome 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.085	N
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.89	L
PhyloP100		-0.49
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.19
Sift	Benign	0.092	T
Sift4G	Benign	0.066	T
Polyphen		0.16	B
Vest4		0.25
MutPred		0.16		Loss of methylation at K140 (P = 0.034)
MVP		0.57
MPC		0.069
ClinPred		0.012	T
GERP RS		-4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.75
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs28943589; hg19: chr5-118813182;