rs1554062352

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_000414.4(HSD17B4):​c.298G>T​(p.Ala100Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

HSD17B4
NM_000414.4 missense

Scores

12
6
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1O:1

Conservation

PhyloP100: 5.39
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.939
PP5
Variant 5-119475723-G-T is Pathogenic according to our data. Variant chr5-119475723-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 556974.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HSD17B4NM_000414.4 linkuse as main transcriptc.298G>T p.Ala100Ser missense_variant 5/24 ENST00000510025.7 NP_000405.1 P51659-1A0A0S2Z4J1B2R659

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HSD17B4ENST00000510025.7 linkuse as main transcriptc.298G>T p.Ala100Ser missense_variant 5/242 NM_000414.4 ENSP00000424940.3 P51659-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
28
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 20, 2023This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 100 of the HSD17B4 protein (p.Ala100Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Perrault syndrome (PMID: 28830375). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 556974). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HSD17B4 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Bifunctional peroxisomal enzyme deficiency Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCounsylMar 01, 2018- -
Perrault syndrome Other:1
not provided, no classification providedliterature onlyGeneReviews-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.47
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.50
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
D;.;.;D;.;.;.;D
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
.;D;D;D;.;D;D;D
M_CAP
Uncertain
0.13
D
MetaRNN
Pathogenic
0.94
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.0
M;.;.;M;.;.;.;.
PrimateAI
Uncertain
0.57
T
PROVEAN
Uncertain
-2.8
D;.;D;.;.;D;.;.
REVEL
Pathogenic
0.90
Sift
Uncertain
0.0040
D;.;D;.;.;D;.;.
Sift4G
Pathogenic
0.0
D;.;D;.;.;D;.;.
Polyphen
1.0
D;.;.;D;.;.;.;D
Vest4
0.64
MutPred
0.83
Gain of glycosylation at A100 (P = 0.0469);Gain of glycosylation at A100 (P = 0.0469);.;Gain of glycosylation at A100 (P = 0.0469);.;.;Gain of glycosylation at A100 (P = 0.0469);.;
MVP
0.94
MPC
0.36
ClinPred
1.0
D
GERP RS
5.7
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.6
Varity_R
0.94
gMVP
0.83

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554062352; hg19: chr5-118811418; API