5-119477621-A-G

Variant names:

• chr5-119477621-A-G
• rs463513
• NM_000414.4:c.434+120A>G

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.434+120A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.529 in 772,406 control chromosomes in the GnomAD database, including 112,033 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20970 hom., cov: 31)
  • Exomes 𝑓: 0.53 (91063 hom.)
• Consequence: HSD17B4 NM_000414.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.00700
• Publications: 9 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 (BayesDel_noAF=-0.96).
• BP6: Variant 5-119477621-A-G is Benign according to our data. Variant chr5-119477621-A-G is described in ClinVar as Benign. ClinVar VariationId is 1185270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.901 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.434+120A>G		intron	N/A	NP_000405.1
	HSD17B4	NM_001199291.3		c.509+120A>G		intron	N/A	NP_001186220.1
	HSD17B4	NM_001374497.1		c.425+129A>G		intron	N/A	NP_001361426.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B4	ENST00000510025.7	TSL:2 MANE Select	c.434+120A>G		intron	N/A	ENSP00000424940.3
	HSD17B4	ENST00000509514.6	TSL:1	c.434+120A>G		intron	N/A	ENSP00000426272.2
	HSD17B4	ENST00000414835.7	TSL:2	c.509+120A>G		intron	N/A	ENSP00000411960.3

Frequencies

GnomAD3 genomes AF: 0.519 AC: 78726 AN: 151804 Hom.: 20940 Cov.: 31

Gnomad AFR AF: 0.494

Gnomad AMI AF: 0.673

Gnomad AMR AF: 0.529

Gnomad ASJ AF: 0.554

Gnomad EAS AF: 0.922

Gnomad SAS AF: 0.529

Gnomad FIN AF: 0.549

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.491

Gnomad OTH AF: 0.539

GnomAD4 exome AF: 0.531 AC: 329492 AN: 620484 Hom.: 91063 Cov.: 7 AF XY: 0.528 AC XY: 177063 AN XY: 335638

African (AFR) AF: 0.502 AC: 8531 AN: 16978

American (AMR) AF: 0.589 AC: 23107 AN: 39214

Ashkenazi Jewish (ASJ) AF: 0.558 AC: 11386 AN: 20402

East Asian (EAS) AF: 0.935 AC: 31816 AN: 34022

South Asian (SAS) AF: 0.501 AC: 33289 AN: 66490

European-Finnish (FIN) AF: 0.557 AC: 28168 AN: 50598

Middle Eastern (MID) AF: 0.508 AC: 2093 AN: 4118

European-Non Finnish (NFE) AF: 0.488 AC: 173984 AN: 356182

Other (OTH) AF: 0.527 AC: 17118 AN: 32480

GnomAD4 genome AF: 0.519 AC: 78807 AN: 151922 Hom.: 20970 Cov.: 31 AF XY: 0.525 AC XY: 38946 AN XY: 74238

African (AFR) AF: 0.494 AC: 20473 AN: 41422

American (AMR) AF: 0.530 AC: 8094 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.554 AC: 1919 AN: 3464

East Asian (EAS) AF: 0.922 AC: 4776 AN: 5178

South Asian (SAS) AF: 0.530 AC: 2548 AN: 4812

European-Finnish (FIN) AF: 0.549 AC: 5782 AN: 10538

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.491 AC: 33332 AN: 67924

Other (OTH) AF: 0.536 AC: 1129 AN: 2108

Alfa AF: 0.504 Hom.: 2516

Bravo AF: 0.520

Asia WGS AF: 0.681 AC: 2362 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bifunctional peroxisomal enzyme deficiency Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Aug 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Perrault syndrome 1 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	3.1
DANN	Benign	0.71
PhyloP100		-0.0070
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs463513; hg19: chr5-118813316;