rs28943594

chr5-119541965-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000414.4(HSD17B4):c.2182A>G(p.Met728Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00629 in 1,612,746 control chromosomes in the GnomAD database, including 401 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (194 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (207 hom.)
• Consequence: HSD17B4 NM_000414.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.51

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000414.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0021131337).
• BP6: Variant 5-119541965-A-G is Benign according to our data. Variant chr5-119541965-A-G is described in ClinVar as [Benign]. Clinvar id is 226670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0939 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD17B4	NM_000414.4	c.2182A>G	p.Met728Val	missense_variant	24/24	ENST00000510025.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD17B4	ENST00000510025.7	c.2182A>G	p.Met728Val	missense_variant	24/24	2	NM_000414.4	P1

Frequencies

GnomAD3 genomes AF: 0.0285 AC: 4328 AN: 152078 Hom.: 192 Cov.: 32

Gnomad AFR AF: 0.0963

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.0197

GnomAD3 exomes AF: 0.00828 AC: 2079 AN: 251230 Hom.: 87 AF XY: 0.00644 AC XY: 875 AN XY: 135790

Gnomad AFR exome AF: 0.0972

Gnomad AMR exome AF: 0.00496

Gnomad ASJ exome AF: 0.00814

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00225

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00397 AC: 5798 AN: 1460550 Hom.: 207 Cov.: 30 AF XY: 0.00364 AC XY: 2648 AN XY: 726662

Gnomad4 AFR exome AF: 0.105

Gnomad4 AMR exome AF: 0.00509

Gnomad4 ASJ exome AF: 0.00889

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00233

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.000973

Gnomad4 OTH exome AF: 0.00767

GnomAD4 genome AF: 0.0285 AC: 4342 AN: 152196 Hom.: 194 Cov.: 32 AF XY: 0.0271 AC XY: 2013 AN XY: 74390

Gnomad4 AFR AF: 0.0964

Gnomad4 AMR AF: 0.0104

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00208

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00125

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.00626 Hom.: 51

Bravo AF: 0.0325

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0920 AC: 405

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.0102 AC: 1234

Asia WGS AF: 0.0100 AC: 37 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00196

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Met753Val in exon 25 of HSD17B4: This variant is not expected to have clinical s ignificance because it has been identified in 9.2% (405/4404) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs28943594). -
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	-	- -

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, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

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	0.075
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	15
Dann	Benign	0.87
DEOGEN2	Benign	0.044	T;.;T;.;.;T;.;T;.;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.091
FATHMM_MKL	Uncertain	0.82	D
MetaRNN	Benign	0.0021	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.78	N;.;N;.;.;.;.;.;.;.
MutationTaster	Benign	0.075	P;P;P;P;P;P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.41	N;N;.;.;N;.;.;N;N;.
REVEL	Benign	0.052
Sift	Benign	0.35	T;T;.;.;T;.;.;T;T;.
Sift4G	Benign	0.32	T;T;.;.;T;.;.;T;T;.
Polyphen		0.0	B;.;B;.;.;B;.;.;B;.
Vest4		0.17
MPC		0.060
ClinPred		0.013	T
GERP RS		3.5
Varity_R		0.077
gMVP		0.38

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

Other links and lift over

dbSNP: rs28943594; hg19: chr5-118877660;