rs775297352
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_000414.4(HSD17B4):āc.1450A>Gā(p.Ile484Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,402,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I484M) has been classified as Uncertain significance.
Frequency
Consequence
NM_000414.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HSD17B4 | NM_000414.4 | c.1450A>G | p.Ile484Val | missense_variant | 17/24 | ENST00000510025.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HSD17B4 | ENST00000510025.7 | c.1450A>G | p.Ile484Val | missense_variant | 17/24 | 2 | NM_000414.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251244Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135796
GnomAD4 exome AF: 0.0000178 AC: 25AN: 1402956Hom.: 0 Cov.: 25 AF XY: 0.0000185 AC XY: 13AN XY: 702094
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 30, 2021 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 484 of the HSD17B4 protein (p.Ile484Val). This variant is present in population databases (rs775297352, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with HSD17B4-related conditions. ClinVar contains an entry for this variant (Variation ID: 227434). 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 not expected to disrupt HSD17B4 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 05, 2016 | p.Ile509Val in exon 18 of HSD17B4: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. O f note, 18 mammals have a valine (Val) at this position despite high nearby amin o acid conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. It has been identified in 1/66664 Eu ropean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadi nstitute.org; dbSNP rs775297352). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at