rs571548182
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000136.3(FANCC):c.733C>T(p.Arg245Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000235 in 1,614,040 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R245Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000136.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCC | NM_000136.3 | c.733C>T | p.Arg245Trp | missense_variant | 8/15 | ENST00000289081.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCC | ENST00000289081.8 | c.733C>T | p.Arg245Trp | missense_variant | 8/15 | 1 | NM_000136.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152164Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251318Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135850
GnomAD4 exome AF: 0.0000192 AC: 28AN: 1461758Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727176
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152282Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6AN XY: 74472
ClinVar
Submissions by phenotype
Fanconi anemia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 15, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 245 of the FANCC protein (p.Arg245Trp). This variant is present in population databases (rs571548182, gnomAD 0.004%). 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: 219908). 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 23, 2018 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 21, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 16, 2022 | 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: 29922827, Gordon2000[Book]) - |
Fanconi anemia complementation group C Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 01, 2021 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 03, 2022 | The p.R245W variant (also known as c.733C>T), located in coding exon 7 of the FANCC gene, results from a C to T substitution at nucleotide position 733. The arginine at codon 245 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at