9-96245352-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The ENST00000375263.8(HSD17B3):c.599C>T(p.Ala200Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000397 in 1,611,610 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A200A) has been classified as Likely benign.
Frequency
Consequence
ENST00000375263.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HSD17B3 | NM_000197.2 | c.599C>T | p.Ala200Val | missense_variant | 8/11 | ENST00000375263.8 | NP_000188.1 | |
SLC35D2-HSD17B3 | NR_182427.1 | n.3366C>T | non_coding_transcript_exon_variant | 23/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HSD17B3 | ENST00000375263.8 | c.599C>T | p.Ala200Val | missense_variant | 8/11 | 1 | NM_000197.2 | ENSP00000364412 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000328 AC: 5AN: 152256Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251332Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135842
GnomAD4 exome AF: 0.0000404 AC: 59AN: 1459354Hom.: 0 Cov.: 30 AF XY: 0.0000454 AC XY: 33AN XY: 726194
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152256Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74388
ClinVar
Submissions by phenotype
Testosterone 17-beta-dehydrogenase deficiency Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 02, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Biochemistry Laboratory, Health Services Laboratory | Nov 20, 2023 | ACMG:PM1 PM2 PP2 PP3 PP5 - |
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 26, 2021 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 200 of the HSD17B3 protein (p.Ala200Val). This variant is present in population databases (rs142236065, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of 17-beta hydroxysteroid dehydrogenase 3 deficiency (PMID: 25740850; Invitae). ClinVar contains an entry for this variant (Variation ID: 435472). 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 HSD17B3 protein function. 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 20, 2024 | Published functional studies demonstrate a deleterious effect on enzymatic function (PMID: 31614207); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36606580, Yazawa2021 [abstract], 25740850, 31614207) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at