rs28943590
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_000414.4(HSD17B4):c.1280C>T(p.Ala427Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,581,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A427A) has been classified as Likely benign.
Frequency
Consequence
NM_000414.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HSD17B4 | NM_000414.4 | c.1280C>T | p.Ala427Val | missense_variant | 15/24 | ENST00000510025.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HSD17B4 | ENST00000510025.7 | c.1280C>T | p.Ala427Val | missense_variant | 15/24 | 2 | NM_000414.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152070Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000327 AC: 82AN: 250798Hom.: 0 AF XY: 0.000199 AC XY: 27AN XY: 135632
GnomAD4 exome AF: 0.0000629 AC: 90AN: 1429908Hom.: 0 Cov.: 24 AF XY: 0.0000434 AC XY: 31AN XY: 713512
GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 152070Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4AN XY: 74276
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 28, 2020 | This variant is associated with the following publications: (PMID: 28649525, 22864515) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 13, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 23, 2020 | The p.Ala452Val variant (rs28943590) has not been reported in the medical literature, or gene specific variation databases. This variant is listed in the Exome Aggregation Consortium Browser with a Latino population frequency of 0.3 percent (identified on 33 out of 11,186 chromosomes). The alanine at position 452 is moderately conserved (considering 12 species) (Alamut v2.8.1) and computational analyses of the effects of the p.Ala452Val variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Ala452Val variant with certainty. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 27, 2019 | Variant classified as Uncertain Significance - Favor Benign. The p.Ala452Val variant in HSD17B4 has not been previously reported in individuals with Perrault syndrome, but has been identified in 0.2% (83/35360) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of this variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BS1_Supporting. - |
Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
HSD17B4-related condition Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 08, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at