rs7437875
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1
The NM_000204.5(CFI):c.1642G>C(p.Glu548Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000546 in 1,614,102 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000204.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CFI | ENST00000394634.7 | c.1642G>C | p.Glu548Gln | missense_variant | Exon 13 of 13 | 1 | NM_000204.5 | ENSP00000378130.2 | ||
ENSG00000285330 | ENST00000645635.1 | c.1534+1488G>C | intron_variant | Intron 12 of 14 | ENSP00000493607.1 |
Frequencies
GnomAD3 genomes AF: 0.00192 AC: 292AN: 152146Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000712 AC: 179AN: 251290Hom.: 0 AF XY: 0.000582 AC XY: 79AN XY: 135794
GnomAD4 exome AF: 0.000404 AC: 590AN: 1461838Hom.: 1 Cov.: 33 AF XY: 0.000378 AC XY: 275AN XY: 727228
GnomAD4 genome AF: 0.00191 AC: 291AN: 152264Hom.: 0 Cov.: 32 AF XY: 0.00192 AC XY: 143AN XY: 74460
ClinVar
Submissions by phenotype
not provided Uncertain:4Benign:1
BS3_supporting -
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Atypical hemolytic-uremic syndrome with I factor anomaly Uncertain:2Benign:1
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
A CFI c.1642G>C (p.Glu548Gln) variant was identified. This variant has been reported in multiple individuals affected with complement related disorders (Chauvet S et al., PMID: 28069603; Fidalgo T al., PMID: 30046676; Osborne AJ et al., PMID: 29500241; de Jong S et al., PMID: 32510551). This variant has been reported in the ClinVar database as a variant of uncertain significance by multiple submitters (ClinVar ID: 347147). Computational predictors are uncertain as to the impact of this variant on CFI function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time. -
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not specified Uncertain:1Benign:1
DNA sequence analysis of the CFI gene demonstrated a sequence change, c.1642G>C, in exon 13 that results in an amino acid change, p.Glu548Gln. This sequence change has been described in the gnomAD database with a relatively high frequency of 0.52% in the African sub-population (dbSNP rs7437875). The p.Glu548Gln change has been reported in an individual with atypical hemolytic uremic syndrome (PMID: 27268256) and an individual with thrombotic thrombocytopenic pupura; however, this individual was also compound heterozygous for two variants in the ADAMTS13 gene (PMID: 30046676). Additionally, a different amino acid change at the same location (p.Glu548Gly) has been reported in association with atypical hemolytic uremic syndrome (PMID: 27268256). The p.Glu548Gln change affects a moderately conserved amino acid residue located in a domain of the CFI protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Glu548Gln substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Glu548Gln change remains unknown at this time. -
Variant summary: CFI c.1642G>C (p.Glu548Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00071 in 251290 control chromosomes, predominantly at a frequency of 0.005 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 50000 fold of the estimated maximal expected allele frequency for a pathogenic variant in CFI causing Genetic Atypical Hemolytic Uremic Syndrome phenotype (1e-07). c.1642G>C has been reported in the literature in individuals affected with Genetic Atypical Hemolytic Uremic Syndrome without evidence of causality (e.g. Gleeson_2016, Brocklebank_2023). These reports do not provide unequivocal conclusions about association of the variant with Genetic Atypical Hemolytic Uremic Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27268256, 37369098). ClinVar contains an entry for this variant (Variation ID: 347147). Based on the evidence outlined above, the variant was classified as likely benign. -
Atypical hemolytic-uremic syndrome Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at