rs758439579
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000136.3(FANCC):c.1023T>G(p.Phe341Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,810 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_000136.3 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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FANCC | NM_000136.3 | c.1023T>G | p.Phe341Leu | missense_variant | Exon 11 of 15 | ENST00000289081.8 | NP_000127.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251224Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135768
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461810Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727190
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Fanconi anemia Uncertain:1
This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 341 of the FANCC protein (p.Phe341Leu). This variant is present in population databases (rs758439579, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with FANCC-related conditions. ClinVar contains an entry for this variant (Variation ID: 1376278). 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 FANCC protein function with a positive 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. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.F341L variant (also known as c.1023T>G), located in coding exon 10 of the FANCC gene, results from a T to G substitution at nucleotide position 1023. The phenylalanine at codon 341 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at