chr4-109740998-GT-G
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePP5_Moderate
The NM_000204.5(CFI):βc.1646delβ(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 (β ).
Frequency
Genomes: π 0.000013 ( 0 hom., cov: 32)
Exomes π: 0.0000027 ( 0 hom. )
Consequence
CFI
NM_000204.5 frameshift
NM_000204.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.40
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 0.0605 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PP5
Variant 4-109740998-GT-G is Pathogenic according to our data. Variant chr4-109740998-GT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1710506.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFI | NM_000204.5 | c.1646del | p.Asn549ThrfsTer25 | frameshift_variant | 13/13 | ENST00000394634.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFI | ENST00000394634.7 | c.1646del | p.Asn549ThrfsTer25 | frameshift_variant | 13/13 | 1 | NM_000204.5 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152192Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461858Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727234
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74356
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
CFI-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Jan 26, 2022 | 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. - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at