9-96235541-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The NM_000197.2(HSD17B3):c.852G>A(p.Trp284*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,762 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
Consequence
NM_000197.2 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HSD17B3 | ENST00000375263.8 | c.852G>A | p.Trp284* | stop_gained | Exon 11 of 11 | 1 | NM_000197.2 | ENSP00000364412.3 | ||
ENSG00000285269 | ENST00000643789.1 | n.*2528G>A | non_coding_transcript_exon_variant | Exon 22 of 22 | ENSP00000494818.1 | |||||
ENSG00000285269 | ENST00000643789.1 | n.*2528G>A | 3_prime_UTR_variant | Exon 22 of 22 | ENSP00000494818.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250920Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135628
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461762Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727158
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1
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. This variant disrupts the C-terminus of the HSD17B3 protein. Other variant(s) that disrupt this region (p.Tyr287*) have been observed in individuals with HSD17B3-related conditions (PMID: 25064799). This suggests that this may be a clinically significant region of the protein. This premature translational stop signal has been observed in individual(s) with 17β-HSD3 deficiency (PMID: 28847746). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Trp284*) in the HSD17B3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 27 amino acid(s) of the HSD17B3 protein. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at