5-119475838-G-A

Variant names:

• chr5-119475838-G-A
• rs25640
• NM_000414.4:c.317G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 4P and 20B. PM1 PM5 BP4_Strong BP6_Very_Strong BA1

The NM_000414.4(HSD17B4):​c.317G>A​(p.Arg106His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.442 in 1,592,192 control chromosomes in the GnomAD database, including 160,587 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R106P) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.39 (12859 hom., cov: 31)
  • Exomes 𝑓: 0.45 (147728 hom.)
• Consequence: HSD17B4 NM_000414.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 7.76
• Publications: 65 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: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen
• Perrault syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Perrault syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000414.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-119475838-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 7657.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=5.040467E-4).
• BP6: Variant 5-119475838-G-A is Benign according to our data. Variant chr5-119475838-G-A is described in ClinVar as Benign. ClinVar VariationId is 198079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.483 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B4	NM_000414.4	MANE Select	c.317G>A	p.Arg106His	missense	Exon 6 of 24	NP_000405.1	A0A0S2Z4J1
	HSD17B4	NM_001199291.3		c.392G>A	p.Arg131His	missense	Exon 7 of 25	NP_001186220.1	P51659-2
	HSD17B4	NM_001374497.1		c.317G>A	p.Arg106His	missense	Exon 6 of 24	NP_001361426.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B4	ENST00000510025.7	TSL:2 MANE Select	c.317G>A	p.Arg106His	missense	Exon 6 of 24	ENSP00000424940.3	P51659-1
	HSD17B4	ENST00000509514.6	TSL:1	c.317G>A	p.Arg106His	missense	Exon 6 of 24	ENSP00000426272.2	E7EPL9
	HSD17B4	ENST00000414835.7	TSL:2	c.392G>A	p.Arg131His	missense	Exon 7 of 25	ENSP00000411960.3	P51659-2

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58717 AN: 151576 Hom.: 12851 Cov.: 31

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.671

Gnomad AMR AF: 0.467

Gnomad ASJ AF: 0.495

Gnomad EAS AF: 0.499

Gnomad SAS AF: 0.366

Gnomad FIN AF: 0.509

Gnomad MID AF: 0.398

Gnomad NFE AF: 0.463

Gnomad OTH AF: 0.417

GnomAD2 exomes AF: 0.451 AC: 113143 AN: 250942 AF XY: 0.446

Gnomad AFR exome AF: 0.164

Gnomad AMR exome AF: 0.559

Gnomad ASJ exome AF: 0.504

Gnomad EAS exome AF: 0.521

Gnomad FIN exome AF: 0.508

Gnomad NFE exome AF: 0.458

Gnomad OTH exome AF: 0.467

GnomAD4 exome AF: 0.447 AC: 644525 AN: 1440498 Hom.: 147728 Cov.: 30 AF XY: 0.445 AC XY: 319459 AN XY: 717768

African (AFR) AF: 0.159 AC: 5303 AN: 33248

American (AMR) AF: 0.552 AC: 24637 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.504 AC: 13082 AN: 25952

East Asian (EAS) AF: 0.463 AC: 18275 AN: 39480

South Asian (SAS) AF: 0.354 AC: 30403 AN: 85798

European-Finnish (FIN) AF: 0.508 AC: 27085 AN: 53290

Middle Eastern (MID) AF: 0.418 AC: 2377 AN: 5688

European-Non Finnish (NFE) AF: 0.455 AC: 497649 AN: 1092700

Other (OTH) AF: 0.431 AC: 25714 AN: 59708

GnomAD4 genome AF: 0.387 AC: 58748 AN: 151694 Hom.: 12859 Cov.: 31 AF XY: 0.390 AC XY: 28905 AN XY: 74096

African (AFR) AF: 0.174 AC: 7217 AN: 41366

American (AMR) AF: 0.468 AC: 7137 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 1718 AN: 3470

East Asian (EAS) AF: 0.499 AC: 2574 AN: 5154

South Asian (SAS) AF: 0.366 AC: 1762 AN: 4810

European-Finnish (FIN) AF: 0.509 AC: 5341 AN: 10498

Middle Eastern (MID) AF: 0.394 AC: 115 AN: 292

European-Non Finnish (NFE) AF: 0.463 AC: 31400 AN: 67838

Other (OTH) AF: 0.415 AC: 875 AN: 2110

Alfa AF: 0.445 Hom.: 66822

Bravo AF: 0.380

TwinsUK AF: 0.468 AC: 1736

ALSPAC AF: 0.470 AC: 1810

ESP6500AA AF: 0.176 AC: 776

ESP6500EA AF: 0.460 AC: 3954

ExAC AF: 0.440 AC: 53356

Asia WGS AF: 0.427 AC: 1472 AN: 3458

EpiCase AF: 0.454

EpiControl AF: 0.455

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Bifunctional peroxisomal enzyme deficiency (3)
-	-	2	not provided (2)
-	-	2	Perrault syndrome 1 (2)
-	-	1	Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.00050	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.99	L
PhyloP100		7.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.012	D
Polyphen		0.98	D
Vest4		0.21
MPC		0.19
ClinPred		0.024	T
GERP RS		5.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.40
gMVP		0.84
Mutation Taster		=254/46	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.12		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: rs25640; hg19: chr5-118811533; COSMIC: COSV56333773; COSMIC: COSV56333773;