5-119525971-G-T

Variant names:

• chr5-119525971-G-T
• rs201009485
• NM_000414.4:c.1628G>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The NM_000414.4(HSD17B4):​c.1628G>T​(p.Arg543Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000959 in 1,459,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R543H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: HSD17B4 NM_000414.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.17
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000414.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-119525971-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 137619.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38897485).

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.1628G>T	p.Arg543Leu	missense	Exon 19 of 24	NP_000405.1
	HSD17B4	NM_001199291.3		c.1703G>T	p.Arg568Leu	missense	Exon 20 of 25	NP_001186220.1
	HSD17B4	NM_001374497.1		c.1619G>T	p.Arg540Leu	missense	Exon 19 of 24	NP_001361426.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B4	ENST00000510025.7	TSL:2 MANE Select	c.1628G>T	p.Arg543Leu	missense	Exon 19 of 24	ENSP00000424940.3
	HSD17B4	ENST00000509514.6	TSL:1	c.1559G>T	p.Arg520Leu	missense	Exon 19 of 24	ENSP00000426272.2
	HSD17B4	ENST00000414835.7	TSL:2	c.1703G>T	p.Arg568Leu	missense	Exon 20 of 25	ENSP00000411960.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000959 AC: 14 AN: 1459406 Hom.: 0 Cov.: 29 AF XY: 0.0000110 AC XY: 8 AN XY: 726172

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1109986

Other (OTH) AF: 0.0000166 AC: 1 AN: 60274

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.65
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.97	N
PhyloP100		5.2
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.26
Sift	Benign	0.054	T
Sift4G	Benign	0.10	T
Polyphen		0.0	B
Vest4		0.31
MutPred		0.73		Loss of MoRF binding (P = 0.0521)
MVP		0.52
MPC		0.088
ClinPred		0.80	D
GERP RS		2.7
Varity_R		0.48
gMVP		0.68
Mutation Taster		=37/63	disease causing

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: rs201009485; hg19: chr5-118861666;