10-102830742-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_ModeratePM2PM5PP3_StrongPP5_Very_Strong
The NM_000102.4(CYP17A1):c.1487G>A(p.Arg496His) variant causes a missense change. The variant allele was found at a frequency of 0.00000374 in 1,602,300 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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R496C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000102.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000659 AC: 1AN: 151736Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000828 AC: 2AN: 241520Hom.: 0 AF XY: 0.00000765 AC XY: 1AN XY: 130670
GnomAD4 exome AF: 0.00000345 AC: 5AN: 1450564Hom.: 0 Cov.: 28 AF XY: 0.00000277 AC XY: 2AN XY: 721620
GnomAD4 genome AF: 0.00000659 AC: 1AN: 151736Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74084
ClinVar
Submissions by phenotype
not provided Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 496 of the CYP17A1 protein (p.Arg496His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with congenital adrenal hyperplasia (PMID: 10720067, 33780934). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CYP17A1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CYP17A1 function (PMID: 10720067). This variant disrupts the p.Arg496 amino acid residue in CYP17A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1515452, 9888582). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Deficiency of steroid 17-alpha-monooxygenase Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at