Genetic Variant HSD17B4:c.622+4959C>G (chr5-119483980-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000414.4(HSD17B4):c.622+4959C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.502 in 151,934 control chromosomes in the GnomAD database, including 20,406 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.50 ( 20406 hom., cov: 32)

Consequence

HSD17B4
NM_000414.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.376

Publications

6 publications found

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 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

HSD17B4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.895 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B4	NM_000414.4 link	c.622+4959C>G		intron_variant	Intron 8 of 23	ENST00000510025.7	NP_000405.1	P51659-1A0A0S2Z4J1B2R659

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B4	ENST00000510025.7 link	c.622+4959C>G		intron_variant	Intron 8 of 23	2	NM_000414.4	ENSP00000424940.3		P51659-1

Frequencies

GnomAD3 genomes

AF:

0.502

AC:

76154

AN:

151816

Hom.:

20394

Cov.:

show subpopulations

Gnomad AFR

AF:

0.319

Gnomad AMI

AF:

0.696

Gnomad AMR

AF:

0.554

Gnomad ASJ

AF:

0.635

Gnomad EAS

AF:

0.917

Gnomad SAS

AF:

0.521

Gnomad FIN

AF:

0.565

Gnomad MID

AF:

0.544

Gnomad NFE

AF:

0.547

Gnomad OTH

AF:

0.530

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.502

AC:

76200

AN:

151934

Hom.:

20406

Cov.:

AF XY:

0.506

AC XY:

37602

AN XY:

74252

show subpopulations

African (AFR)

AF:

0.320

AC:

13235

AN:

41420

American (AMR)

AF:

0.555

AC:

8464

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.635

AC:

2202

AN:

3468

East Asian (EAS)

AF:

0.917

AC:

4746

AN:

5176

South Asian (SAS)

AF:

0.521

AC:

2507

AN:

4814

European-Finnish (FIN)

AF:

0.565

AC:

5952

AN:

10538

Middle Eastern (MID)

AF:

0.544

AC:

160

AN:

294

European-Non Finnish (NFE)

AF:

0.547

AC:

37191

AN:

67938

Other (OTH)

AF:

0.525

AC:

1108

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1831

3663

5494

7326

9157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

694

1388

2082

2776

3470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.519

Hom.:

2619

Bravo

AF:

0.497

Asia WGS

AF:

0.658

AC:

2286

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

3.5

(source)

DANN

Benign

0.76

PhyloP100

-0.38

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over