rs28943592

Variant names:

• chr5-119536489-C-T
• rs28943592
• NM_000414.4:c.2060C>T

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.2060C>T​(p.Thr687Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,611,912 control chromosomes in the GnomAD database, including 180 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T687T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0036 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (167 hom.)
• Consequence: HSD17B4 NM_000414.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.37
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038492382).
• BP6: Variant 5-119536489-C-T is Benign according to our data. Variant chr5-119536489-C-T is described in ClinVar as Benign. ClinVar VariationId is 226669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0731 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.2060C>T	p.Thr687Ile	missense	Exon 23 of 24	NP_000405.1	A0A0S2Z4J1
	HSD17B4	NM_001199291.3		c.2135C>T	p.Thr712Ile	missense	Exon 24 of 25	NP_001186220.1	P51659-2
	HSD17B4	NM_001374497.1		c.2051C>T	p.Thr684Ile	missense	Exon 23 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.2060C>T	p.Thr687Ile	missense	Exon 23 of 24	ENSP00000424940.3	P51659-1
	HSD17B4	ENST00000509514.6	TSL:1	c.1991C>T	p.Thr664Ile	missense	Exon 23 of 24	ENSP00000426272.2	E7EPL9
	HSD17B4	ENST00000414835.7	TSL:2	c.2135C>T	p.Thr712Ile	missense	Exon 24 of 25	ENSP00000411960.3	P51659-2

Frequencies

GnomAD3 genomes AF: 0.00365 AC: 555 AN: 152082 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.0796

Gnomad SAS AF: 0.00868

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00699 AC: 1756 AN: 251164 AF XY: 0.00682

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00595

Gnomad EAS exome AF: 0.0800

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00309 AC: 4517 AN: 1459712 Hom.: 167 Cov.: 30 AF XY: 0.00321 AC XY: 2332 AN XY: 726222

African (AFR) AF: 0.000150 AC: 5 AN: 33400

American (AMR) AF: 0.0000672 AC: 3 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.00602 AC: 157 AN: 26076

East Asian (EAS) AF: 0.0850 AC: 3370 AN: 39658

South Asian (SAS) AF: 0.00437 AC: 377 AN: 86226

European-Finnish (FIN) AF: 0.00133 AC: 71 AN: 53392

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.000222 AC: 246 AN: 1110300

Other (OTH) AF: 0.00474 AC: 286 AN: 60286

GnomAD4 genome AF: 0.00363 AC: 553 AN: 152200 Hom.: 13 Cov.: 32 AF XY: 0.00429 AC XY: 319 AN XY: 74426

African (AFR) AF: 0.000578 AC: 24 AN: 41558

American (AMR) AF: 0.0000655 AC: 1 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.0794 AC: 411 AN: 5176

South Asian (SAS) AF: 0.00869 AC: 42 AN: 4832

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 67966

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00102 Hom.: 1

Bravo AF: 0.00422

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00672 AC: 816

Asia WGS AF: 0.0380 AC: 133 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Bifunctional peroxisomal enzyme deficiency (1)
-	-	1	Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome (1)
-	-	1	Bifunctional peroxisomal enzyme deficiency;C4551721:Perrault syndrome 1 (1)
-	-	1	not provided (1)
-	-	1	Perrault syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.4
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.23
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.019	D
Polyphen		0.59	P
Vest4		0.28
MVP		0.62
MPC		0.17
ClinPred		0.031	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.56
gMVP		0.76
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs28943592; hg19: chr5-118872184; COSMIC: COSV56338408;