5-119475838-G-C

Position:

• chr5-119475838-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000414.4(HSD17B4):​c.317G>C​(p.Arg106Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R106H) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HSD17B4 NM_000414.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.76

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929
• PP5: Variant 5-119475838-G-C is Pathogenic according to our data. Variant chr5-119475838-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 7657.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-119475838-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSD17B4	NM_000414.4	c.317G>C	p.Arg106Pro	missense_variant	6/24	ENST00000510025.7	NP_000405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSD17B4	ENST00000510025.7	c.317G>C	p.Arg106Pro	missense_variant	6/24	2	NM_000414.4	ENSP00000424940	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447506 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 721004

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.10e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Bifunctional peroxisomal enzyme deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2001

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.;.;D;.;.;.;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D;D;.;D;D;D
M_CAP	Uncertain	0.094	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	0.88	L;.;.;L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-4.1	D;.;D;.;.;D;.;.
REVEL	Pathogenic	0.89
Sift	Uncertain	0.015	D;.;D;.;.;D;.;.
Sift4G	Uncertain	0.011	D;.;D;.;.;D;.;.
Polyphen		0.97	D;.;.;D;.;.;.;D
Vest4		0.56
MutPred		0.78		Loss of MoRF binding (P = 0.0694);Loss of MoRF binding (P = 0.0694);.;Loss of MoRF binding (P = 0.0694);.;.;Loss of MoRF binding (P = 0.0694);.;
MVP		0.94
MPC		0.31
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.91
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs25640; hg19: chr5-118811533;