rs1445308792
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePP5_Moderate
The NM_000204.5(CFI):c.1646delA(p.Asn549ThrfsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Consequence
NM_000204.5 frameshift
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 |
---|---|---|---|---|---|---|---|---|---|---|
CFI | ENST00000394634.7 | c.1646delA | p.Asn549ThrfsTer25 | frameshift_variant | Exon 13 of 13 | 1 | NM_000204.5 | ENSP00000378130.2 | ||
ENSG00000285330 | ENST00000645635.1 | c.1534+1492delA | intron_variant | Intron 12 of 14 | ENSP00000493607.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152192Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461858Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727234
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74356
ClinVar
Submissions by phenotype
CFI-related disorder Pathogenic:1
This frameshift variant is found in the last exon of CFI and it is therefore predicted to escape nonsense-mediated mRNA decay (NMD). However, frameshift variants located downstream of this variant have been reported as disease-causing variants in the literature (PMID: 31440263, 24036952). This variant has not been previously reported or functionally characterized in the literature to our knowledge. Loss-of-function variation in CFI has been reported in individuals with complement factor I deficiency in the literature (PMID: 32853637, 31231365, 22710145); however, loss-of-function as a mechanism of disease has not yet been well established. The c.1646del (p.Asn549ThrfsTer25) variant is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.1646del (p.Asn549ThrfsTer25) variant is classified as Likely Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at