chr4-109741002-TC-T
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_000204.5(CFI):βc.1642delβ(p.Glu548LysfsTer26) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000124 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β ).
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 32)
Exomes π: 6.8e-7 ( 0 hom. )
Consequence
CFI
NM_000204.5 frameshift
NM_000204.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.88
Genes affected
CFI (HGNC:5394): (complement factor I) This gene encodes a serine proteinase that is essential for regulating the complement cascade. The encoded preproprotein is cleaved to produce both heavy and light chains, which are linked by disulfide bonds to form a heterodimeric glycoprotein. This heterodimer can cleave and inactivate the complement components C4b and C3b, and it prevents the assembly of the C3 and C5 convertase enzymes. Defects in this gene cause complement factor I deficiency, an autosomal recessive disease associated with a susceptibility to pyogenic infections. Mutations in this gene have been associated with a predisposition to atypical hemolytic uremic syndrome, a disease characterized by acute renal failure, microangiopathic hemolytic anemia and thrombocytopenia. Primary glomerulonephritis with immune deposits and age-related macular degeneration are other conditions associated with mutations of this gene. [provided by RefSeq, Dec 2015]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0628 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFI | NM_000204.5 | c.1642del | p.Glu548LysfsTer26 | frameshift_variant | 13/13 | ENST00000394634.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFI | ENST00000394634.7 | c.1642del | p.Glu548LysfsTer26 | frameshift_variant | 13/13 | 1 | NM_000204.5 | P2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152092Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461862Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727238
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152092Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74298
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 17, 2023 | This sequence change creates a premature translational stop signal (p.Glu548Lysfs*26) in the CFI gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 36 amino acid(s) of the CFI protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CFI-related conditions. ClinVar contains an entry for this variant (Variation ID: 1972463). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at