chr17-17215010-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_ModerateBP6BS2_Supporting
The NM_144997.7(FLCN):c.1513G>A(p.Val505Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V505A) has been classified as Uncertain significance.
Frequency
Consequence
NM_144997.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FLCN | ENST00000285071.9 | c.1513G>A | p.Val505Ile | missense_variant | Exon 13 of 14 | 1 | NM_144997.7 | ENSP00000285071.4 | ||
ENSG00000264187 | ENST00000427497.3 | n.*347G>A | non_coding_transcript_exon_variant | Exon 9 of 12 | 1 | ENSP00000394249.3 | ||||
ENSG00000264187 | ENST00000427497.3 | n.*347G>A | 3_prime_UTR_variant | Exon 9 of 12 | 1 | ENSP00000394249.3 | ||||
MPRIP | ENST00000578209.5 | c.*18-2480C>T | intron_variant | Intron 5 of 5 | 3 | ENSP00000464276.1 |
Frequencies
GnomAD3 genomes AF: 0.0000328 AC: 5AN: 152224Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251478Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135910
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461836Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18AN XY: 727214
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152224Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74370
ClinVar
Submissions by phenotype
not specified Uncertain:1
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not provided Uncertain:1
In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Birt-Hogg-Dube syndrome Uncertain:1
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 505 of the FLCN protein (p.Val505Ile). This variant is present in population databases (rs376715412, gnomAD 0.01%). 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: 409376). 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 not expected to disrupt FLCN protein function with a negative predictive value of 80%. 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. -
Birt-Hogg-Dube syndrome 1 Benign:1
This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Hereditary cancer-predisposing syndrome Benign:1
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at