rs140336749
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM1PP5_Very_StrongBP4
The NM_000497.4(CYP11B1):c.427C>T(p.Arg143Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000613 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R143L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000497.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP11B1 | NM_000497.4 | c.427C>T | p.Arg143Trp | missense_variant | 3/9 | ENST00000292427.10 | |
CYP11B1 | NM_001026213.1 | c.427C>T | p.Arg143Trp | missense_variant | 3/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP11B1 | ENST00000292427.10 | c.427C>T | p.Arg143Trp | missense_variant | 3/9 | 1 | NM_000497.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152206Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000160 AC: 40AN: 250704Hom.: 0 AF XY: 0.000236 AC XY: 32AN XY: 135518
GnomAD4 exome AF: 0.0000636 AC: 93AN: 1461692Hom.: 0 Cov.: 40 AF XY: 0.0000963 AC XY: 70AN XY: 727120
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152324Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6AN XY: 74472
ClinVar
Submissions by phenotype
Deficiency of steroid 11-beta-monooxygenase Pathogenic:3Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant p.R143W in CYP11B1 (NM_000497.4) has been previously reported in affected patients (Mooji CF et al). Functional studies show a damaging effect (Menabo S et al). The variant has been submitted to ClinVar as Likely Pathogenic.In silico tools predict a damaging effect and the residue is conserved across species. For these reasons, this variant has been classified as Pathogenic - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 26, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 12, 2024 | - - |
not provided, no classification provided | literature only | Pediatric Endocrinology Laboratory; Christian Albrechts University of Kiel | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 21, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 143 of the CYP11B1 protein (p.Arg143Trp). This variant is present in population databases (rs140336749, gnomAD 0.1%). This missense change has been observed in individuals with clinical features of adrenal hyperplasia (PMID: 23940125, 24022297, 26053152). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 56831). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CYP11B1 protein function. Experimental studies have shown that this missense change affects CYP11B1 function (PMID: 23940125). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at