17-17216401-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_144997.7(FLCN):c.1279C>A(p.Pro427Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000263 in 152,170 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 Uncertain significance (★★).
Frequency
Consequence
NM_144997.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FLCN | ENST00000285071.9 | c.1279C>A | p.Pro427Thr | missense_variant | Exon 11 of 14 | 1 | NM_144997.7 | ENSP00000285071.4 | ||
ENSG00000264187 | ENST00000427497.3 | n.*113C>A | non_coding_transcript_exon_variant | Exon 7 of 12 | 1 | ENSP00000394249.3 | ||||
ENSG00000264187 | ENST00000427497.3 | n.*113C>A | 3_prime_UTR_variant | Exon 7 of 12 | 1 | ENSP00000394249.3 | ||||
MPRIP | ENST00000578209.5 | c.*18-1089G>T | intron_variant | Intron 5 of 5 | 3 | ENSP00000464276.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000403 AC: 1AN: 248316Hom.: 0 AF XY: 0.00000743 AC XY: 1AN XY: 134676
GnomAD4 exome Cov.: 31
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74348
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
The p.P427T variant (also known as c.1279C>A), located in coding exon 8 of the FLCN gene, results from a C to A substitution at nucleotide position 1279. The proline at codon 427 is replaced by threonine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
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not provided Uncertain:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 17028174) -
Birt-Hogg-Dube syndrome Uncertain:1
This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 427 of the FLCN protein (p.Pro427Thr). This variant is present in population databases (rs773986076, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with FLCN-related conditions. ClinVar contains an entry for this variant (Variation ID: 485631). 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) has been performed 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 FLCN protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at