chr4-109764531-G-T
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000204.5(CFI):c.482+6C>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 1,613,784 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.012 ( 50 hom., cov: 32)
Exomes 𝑓: 0.0012 ( 33 hom. )
Consequence
CFI
NM_000204.5 splice_donor_region, intron
NM_000204.5 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.001161
2
Clinical Significance
Conservation
PhyloP100: 0.452
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 Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
BP6
?
Variant 4-109764531-G-T is Benign according to our data. Variant chr4-109764531-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 717208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0122 (1850/152152) while in subpopulation AFR AF= 0.0421 (1749/41496). AF 95% confidence interval is 0.0405. There are 50 homozygotes in gnomad4. There are 875 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd at 50 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFI | NM_000204.5 | c.482+6C>A | splice_donor_region_variant, intron_variant | ENST00000394634.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFI | ENST00000394634.7 | c.482+6C>A | splice_donor_region_variant, intron_variant | 1 | NM_000204.5 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0122 AC: 1852AN: 152034Hom.: 50 Cov.: 32
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GnomAD3 exomes AF: 0.00318 AC: 799AN: 251368Hom.: 15 AF XY: 0.00236 AC XY: 321AN XY: 135860
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GnomAD4 exome AF: 0.00120 AC: 1755AN: 1461632Hom.: 33 Cov.: 31 AF XY: 0.00105 AC XY: 764AN XY: 727140
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Atypical hemolytic-uremic syndrome with I factor anomaly Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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 provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Atypical hemolytic-uremic syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Nov 03, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 6
Find out detailed SpliceAI scores and Pangolin per-transcript scores at