chr4-109740912-A-G
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_000204.5(CFI):āc.1733T>Cā(p.Ile578Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,613,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000033 ( 0 hom., cov: 32)
Exomes š: 0.000043 ( 0 hom. )
Consequence
CFI
NM_000204.5 missense
NM_000204.5 missense
Scores
2
10
7
Clinical Significance
Conservation
PhyloP100: 7.79
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 Likely_benign. Variant got -1 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.4200296).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFI | NM_000204.5 | c.1733T>C | p.Ile578Thr | missense_variant | 13/13 | ENST00000394634.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFI | ENST00000394634.7 | c.1733T>C | p.Ile578Thr | missense_variant | 13/13 | 1 | NM_000204.5 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000328 AC: 5AN: 152238Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251352Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135860
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GnomAD4 exome AF: 0.0000431 AC: 63AN: 1461726Hom.: 0 Cov.: 32 AF XY: 0.0000330 AC XY: 24AN XY: 727182
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GnomAD4 genome AF: 0.0000328 AC: 5AN: 152238Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74364
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 28, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 24, 2022 | 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 not expected to disrupt CFI protein function. ClinVar contains an entry for this variant (Variation ID: 1509573). This missense change has been observed in individual(s) with atypical hemolytic uremic syndrome and/or macular degeneration (PMID: 24036952, 27268256). This variant is present in population databases (rs760148430, gnomAD 0.02%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 578 of the CFI protein (p.Ile578Thr). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
N;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;D;D
Vest4
MutPred
0.51
.;Gain of disorder (P = 0.0111);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at