rs121434534
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3_StrongPP5_Moderate
The NM_000103.4(CYP19A1):c.1303C>T(p.Arg435Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000756 in 1,588,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_000103.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CYP19A1 | NM_000103.4 | c.1303C>T | p.Arg435Cys | missense_variant | 10/10 | ENST00000396402.6 | NP_000094.2 | |
MIR4713HG | NR_146310.1 | n.195-66966G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CYP19A1 | ENST00000396402.6 | c.1303C>T | p.Arg435Cys | missense_variant | 10/10 | 1 | NM_000103.4 | ENSP00000379683 | P1 | |
MIR4713HG | ENST00000559909.1 | n.195-66966G>A | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152138Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250788Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135502
GnomAD4 exome AF: 0.00000557 AC: 8AN: 1436048Hom.: 0 Cov.: 26 AF XY: 0.00000698 AC XY: 5AN XY: 716092
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152138Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74324
ClinVar
Submissions by phenotype
Aromatase deficiency Pathogenic:2
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 15, 1993 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 09, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 435 of the CYP19A1 protein (p.Arg435Cys). This variant is present in population databases (rs121434534, gnomAD 0.006%). This missense change has been observed in individuals with aromatase deficiency (PMID: 8265607, 17164303, 23329769, 27256151). ClinVar contains an entry for this variant (Variation ID: 17815). 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 CYP19A1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CYP19A1 function (PMID: 8265607, 17164303). 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