rs1554828492
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PM5BP4
The NM_000136.3(FANCC):c.1330G>A(p.Val444Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. V444F) has been classified as Uncertain significance.
Frequency
Consequence
NM_000136.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCC | NM_000136.3 | c.1330G>A | p.Val444Ile | missense_variant, splice_region_variant | 14/15 | ENST00000289081.8 | |
LOC107987102 | XR_001746847.2 | n.687C>T | non_coding_transcript_exon_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCC | ENST00000289081.8 | c.1330G>A | p.Val444Ile | missense_variant, splice_region_variant | 14/15 | 1 | NM_000136.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Fanconi anemia Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 11, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2017 | This sequence change replaces valine with isoleucine at codon 444 of the FANCC protein (p.Val444Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. It also falls at the first nucleotide of exon 14 of the FANCC coding sequence. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FANCC-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 31, 2023 | The c.1330G>A (p.V444I) alteration is located in exon 14 (coding exon 13) of the FANCC gene. This alteration results from a G to A substitution at nucleotide position 1330, causing the valine (V) at amino acid position 444 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at