1-119422565-G-A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000198.4(HSD3B2):c.1064G>A(p.Trp355*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,768 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_000198.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HSD3B2 | NM_000198.4 | c.1064G>A | p.Trp355* | stop_gained | Exon 4 of 4 | ENST00000369416.4 | NP_000189.1 | |
HSD3B2 | NM_001166120.2 | c.1064G>A | p.Trp355* | stop_gained | Exon 4 of 4 | NP_001159592.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250916Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135614
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461768Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727188
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
3 beta-Hydroxysteroid dehydrogenase deficiency Pathogenic:2
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The p.Trp355X variant in HSD3B2 has been reported in a homozygous individual wit h clinical features of 3-beta (?)-hydroxysteroid dehydrogenase (HSD) deficiency (Welzel 2008). The p.Trp355X variant has been identified in 1/6498 of South Asia n chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org; dbSNP rs767128094). This nonsense variant leads to a premature terminat ion codon at position 355, which is predicted to lead to a truncated or absent p rotein. Biallelic loss of function of the HSD3B2 gene has been associated with H SD deficiency. In vitro studies provide evidence that this variant leads to a tr uncated protein which impacts protein function (Welzel 2008). However, these typ es of assays may not accurately represent biological function. In summary, alth ough additional studies are required to fully establish a null effect on the pro tein, the p.Trp355X variant in HSD3B2 is likely pathogenic for 3-beta (?)-hydrox ysteroid dehydrogenase (HSD) deficiency in an autosomal recessive manner based u pon its predicted impact on protein function. -
Congenital adrenal hyperplasia Pathogenic:1
Variant summary: HSD3B2 c.1064G>A (p.Trp355X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been in association with Adrenal hyperplasia and 3 beta-hydroxysteroid dehydrogenase deficiency in HGMD. The variant allele was found at a frequency of 8e-06 in 250916 control chromosomes. c.1064G>A has been reported in the literature in an individual affected with Congenital Adrenal Hyperplasia (Welzel_2008). These data indicate that the variant is likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein expression and enzymatic activity, resulting in <10% of normal activity and no or very little protein expression in the absence of a proteasome inhibitor (Welzel_2008). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at