rs11205

Variant names:

• chr5-119526018-A-G
• rs11205
• NM_000414.4:c.1675A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-119526018-A-G
• chr5-119526018-A-C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000414.4(HSD17B4):​c.1675A>G​(p.Ile559Val) variant causes a missense change. The variant allele was found at a frequency of 0.402 in 1,540,756 control chromosomes in the GnomAD database, including 126,774 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (12811 hom., cov: 32)
  • Exomes 𝑓: 0.40 (113963 hom.)
• Consequence: HSD17B4 NM_000414.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 4.20
• Publications: 56 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 -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 3 benign, 14 uncertain in NM_000414.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0011920929).
• BP6: Variant 5-119526018-A-G is Benign according to our data. Variant chr5-119526018-A-G is described in ClinVar as Benign. ClinVar VariationId is 226667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.442 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.1675A>G	p.Ile559Val	missense	Exon 19 of 24	NP_000405.1	A0A0S2Z4J1
	HSD17B4	NM_001199291.3		c.1750A>G	p.Ile584Val	missense	Exon 20 of 25	NP_001186220.1	P51659-2
	HSD17B4	NM_001374497.1		c.1666A>G	p.Ile556Val	missense	Exon 19 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.1675A>G	p.Ile559Val	missense	Exon 19 of 24	ENSP00000424940.3	P51659-1
	HSD17B4	ENST00000509514.6	TSL:1	c.1606A>G	p.Ile536Val	missense	Exon 19 of 24	ENSP00000426272.2	E7EPL9
	HSD17B4	ENST00000414835.7	TSL:2	c.1750A>G	p.Ile584Val	missense	Exon 20 of 25	ENSP00000411960.3	P51659-2

Frequencies

GnomAD3 genomes AF: 0.408 AC: 61907 AN: 151660 Hom.: 12803 Cov.: 32

Gnomad AFR AF: 0.386

Gnomad AMI AF: 0.440

Gnomad AMR AF: 0.451

Gnomad ASJ AF: 0.452

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.498

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.404

Gnomad OTH AF: 0.398

GnomAD2 exomes AF: 0.418 AC: 105063 AN: 251098 AF XY: 0.405

Gnomad AFR exome AF: 0.387

Gnomad AMR exome AF: 0.527

Gnomad ASJ exome AF: 0.455

Gnomad EAS exome AF: 0.414

Gnomad FIN exome AF: 0.504

Gnomad NFE exome AF: 0.407

Gnomad OTH exome AF: 0.411

GnomAD4 exome AF: 0.402 AC: 557757 AN: 1388978 Hom.: 113963 Cov.: 24 AF XY: 0.397 AC XY: 276028 AN XY: 695156

African (AFR) AF: 0.380 AC: 12168 AN: 32006

American (AMR) AF: 0.519 AC: 23128 AN: 44534

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 11863 AN: 25688

East Asian (EAS) AF: 0.362 AC: 14224 AN: 39276

South Asian (SAS) AF: 0.285 AC: 24164 AN: 84844

European-Finnish (FIN) AF: 0.503 AC: 26833 AN: 53366

Middle Eastern (MID) AF: 0.371 AC: 2080 AN: 5604

European-Non Finnish (NFE) AF: 0.402 AC: 420103 AN: 1045798

Other (OTH) AF: 0.401 AC: 23194 AN: 57862

GnomAD4 genome AF: 0.408 AC: 61948 AN: 151778 Hom.: 12811 Cov.: 32 AF XY: 0.411 AC XY: 30483 AN XY: 74152

African (AFR) AF: 0.386 AC: 15982 AN: 41432

American (AMR) AF: 0.451 AC: 6871 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 1566 AN: 3466

East Asian (EAS) AF: 0.408 AC: 2109 AN: 5170

South Asian (SAS) AF: 0.303 AC: 1463 AN: 4824

European-Finnish (FIN) AF: 0.498 AC: 5215 AN: 10468

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.404 AC: 27397 AN: 67880

Other (OTH) AF: 0.397 AC: 837 AN: 2106

Alfa AF: 0.405 Hom.: 28042

Bravo AF: 0.411

TwinsUK AF: 0.421 AC: 1560

ALSPAC AF: 0.407 AC: 1569

ESP6500AA AF: 0.395 AC: 1741

ESP6500EA AF: 0.409 AC: 3518

ExAC AF: 0.410 AC: 49838

Asia WGS AF: 0.381 AC: 1319 AN: 3472

EpiCase AF: 0.400

EpiControl AF: 0.398

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Bifunctional peroxisomal enzyme deficiency (4)
-	-	4	not specified (4)
-	-	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	0.071
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.093	T
Eigen	Benign	0.052
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.29
Sift	Benign	0.28	T
Sift4G	Benign	0.18	T
Polyphen		0.12	B
Vest4		0.16
MPC		0.10
ClinPred		0.015	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.42
Mutation Taster		=96/4	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: rs11205; hg19: chr5-118861713; COSMIC: COSV56333537; COSMIC: COSV56333537;