chr4-109740936-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_000204.5(CFI):ā€‹c.1709G>Cā€‹(p.Ser570Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000072 ( 0 hom., cov: 33)
Exomes š‘“: 0.00016 ( 0 hom. )

Consequence

CFI
NM_000204.5 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 2.90
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.38782194).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CFINM_000204.5 linkuse as main transcriptc.1709G>C p.Ser570Thr missense_variant 13/13 ENST00000394634.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CFIENST00000394634.7 linkuse as main transcriptc.1709G>C p.Ser570Thr missense_variant 13/131 NM_000204.5 P2

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152180
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000597
AC:
15
AN:
251406
Hom.:
0
AF XY:
0.0000736
AC XY:
10
AN XY:
135868
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000132
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000164
AC:
240
AN:
1461846
Hom.:
0
Cov.:
33
AF XY:
0.000164
AC XY:
119
AN XY:
727230
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000213
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152180
Hom.:
0
Cov.:
33
AF XY:
0.0000673
AC XY:
5
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000109
Hom.:
0
Bravo
AF:
0.0000680
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.000273
EpiControl
AF:
0.000356

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Atypical hemolytic-uremic syndrome with I factor anomaly Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, no assertion criteria providedclinical testingBioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic HealthcareApr 20, 2017- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeOct 14, 2022This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 570 of the CFI protein (p.Ser570Thr). This variant is present in population databases (rs200973120, gnomAD 0.01%). This missense change has been observed in individual(s) with CFH-related conditions (PMID: 29888403). ClinVar contains an entry for this variant (Variation ID: 438686). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CFI protein function. 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. -
Atypical hemolytic-uremic syndrome with I factor anomaly;C3463916:Factor I deficiency;C3809523:Age related macular degeneration 13 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsFeb 04, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Benign
-0.085
T
BayesDel_noAF
Benign
-0.12
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.33
T;T;.
Eigen
Benign
0.16
Eigen_PC
Benign
0.18
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.25
T;T;T
M_CAP
Uncertain
0.13
D
MetaRNN
Benign
0.39
T;T;T
MetaSVM
Uncertain
0.41
D
MutationAssessor
Benign
0.40
N;.;.
MutationTaster
Benign
0.96
N;N;N
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-1.8
N;N;N
REVEL
Uncertain
0.46
Sift
Benign
0.041
D;D;T
Sift4G
Benign
0.17
T;T;T
Polyphen
1.0
D;D;P
Vest4
0.43
MutPred
0.45
.;Gain of helix (P = 0.2294);.;
MVP
0.89
MPC
0.35
ClinPred
0.28
T
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.66
gMVP
0.56

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200973120; hg19: chr4-110662092; API