5-119452576-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_001199291.3(HSD17B4):​c.-178A>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,750 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 Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

HSD17B4
NM_001199291.3 5_prime_UTR_premature_start_codon_gain

Scores

5
6
5

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.92
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 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.986
PP5
Variant 5-119452576-A-C is Pathogenic according to our data. Variant chr5-119452576-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 859562.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HSD17B4NM_000414.4 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 24 ENST00000510025.7 NP_000405.1 P51659-1A0A0S2Z4J1B2R659

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HSD17B4ENST00000510025.7 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 24 2 NM_000414.4 ENSP00000424940.3 P51659-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461750
Hom.:
0
Cov.:
34
AF XY:
0.00000138
AC XY:
1
AN XY:
727194
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome Pathogenic:1
Feb 13, 2019
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change affects the initiator methionine of the HSD17B4 mRNA. The next in-frame methionine is located at codon p.148. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with HSD17B4-related conditions. This variant disrupts the p.Gly16 amino acid residue in HSD17B4. Other variant(s) that disrupt this residue have been observed in individuals with HSD17B4-related conditions (PMID: 9482850, 25967389, 27290639, 26970254, 16385454, 9915948), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.32
CADD
Uncertain
24
DANN
Benign
0.96
DEOGEN2
Benign
0.20
T;.;.;T;.
Eigen
Uncertain
0.33
Eigen_PC
Uncertain
0.30
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.90
.;D;D;D;D
M_CAP
Pathogenic
0.76
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D
MetaSVM
Uncertain
0.18
D
PROVEAN
Benign
-1.1
N;.;N;N;.
REVEL
Uncertain
0.60
Sift
Pathogenic
0.0
D;.;D;D;.
Sift4G
Benign
0.11
T;.;T;.;.
Polyphen
0.98
D;.;.;D;.
Vest4
0.75
MutPred
0.96
Loss of MoRF binding (P = 0.0755);Loss of MoRF binding (P = 0.0755);Loss of MoRF binding (P = 0.0755);Loss of MoRF binding (P = 0.0755);Loss of MoRF binding (P = 0.0755);
MVP
0.81
ClinPred
0.99
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.97

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs1488399880; hg19: chr5-118788271; API