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GeneBe

rs641153

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001710.6(CFB):c.95G>A(p.Arg32Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0989 in 1,612,870 control chromosomes in the GnomAD database, including 8,814 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R32W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.12 ( 1207 hom., cov: 31)
Exomes 𝑓: 0.097 ( 7607 hom. )

Consequence

CFB
NM_001710.6 missense

Scores

16

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: -2.31
Variant links:
Genes affected
CFB (HGNC:1037): (complement factor B) This gene encodes complement factor B, a component of the alternative pathway of complement activation. Factor B circulates in the blood as a single chain polypeptide. Upon activation of the alternative pathway, it is cleaved by complement factor D yielding the noncatalytic chain Ba and the catalytic subunit Bb. The active subunit Bb is a serine protease which associates with C3b to form the alternative pathway C3 convertase. Bb is involved in the proliferation of preactivated B lymphocytes, while Ba inhibits their proliferation. This gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. This cluster includes several genes involved in regulation of the immune reaction. Polymorphisms in this gene are associated with a reduced risk of age-related macular degeneration. The polyadenylation site of this gene is 421 bp from the 5' end of the gene for complement component 2. [provided by RefSeq, Jul 2008]

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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 (MetaRNN=0.001252532).
BP6
Variant 6-31946403-G-A is Benign according to our data. Variant chr6-31946403-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 16075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-31946403-G-A is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CFBNM_001710.6 linkuse as main transcriptc.95G>A p.Arg32Gln missense_variant 2/18 ENST00000425368.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CFBENST00000425368.7 linkuse as main transcriptc.95G>A p.Arg32Gln missense_variant 2/181 NM_001710.6 P1P00751-1

Frequencies

GnomAD3 genomes
AF:
0.116
AC:
17666
AN:
152026
Hom.:
1209
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.190
Gnomad AMI
AF:
0.0461
Gnomad AMR
AF:
0.100
Gnomad ASJ
AF:
0.0574
Gnomad EAS
AF:
0.0624
Gnomad SAS
AF:
0.134
Gnomad FIN
AF:
0.0579
Gnomad MID
AF:
0.0886
Gnomad NFE
AF:
0.0902
Gnomad OTH
AF:
0.129
GnomAD3 exomes
AF:
0.0960
AC:
23669
AN:
246556
Hom.:
1358
AF XY:
0.0987
AC XY:
13261
AN XY:
134396
show subpopulations
Gnomad AFR exome
AF:
0.191
Gnomad AMR exome
AF:
0.0702
Gnomad ASJ exome
AF:
0.0522
Gnomad EAS exome
AF:
0.0619
Gnomad SAS exome
AF:
0.156
Gnomad FIN exome
AF:
0.0635
Gnomad NFE exome
AF:
0.0902
Gnomad OTH exome
AF:
0.103
GnomAD4 exome
AF:
0.0971
AC:
141800
AN:
1460726
Hom.:
7607
Cov.:
34
AF XY:
0.0979
AC XY:
71130
AN XY:
726674
show subpopulations
Gnomad4 AFR exome
AF:
0.188
Gnomad4 AMR exome
AF:
0.0734
Gnomad4 ASJ exome
AF:
0.0555
Gnomad4 EAS exome
AF:
0.0736
Gnomad4 SAS exome
AF:
0.149
Gnomad4 FIN exome
AF:
0.0650
Gnomad4 NFE exome
AF:
0.0942
Gnomad4 OTH exome
AF:
0.108
GnomAD4 genome
AF:
0.116
AC:
17688
AN:
152144
Hom.:
1207
Cov.:
31
AF XY:
0.114
AC XY:
8486
AN XY:
74382
show subpopulations
Gnomad4 AFR
AF:
0.191
Gnomad4 AMR
AF:
0.100
Gnomad4 ASJ
AF:
0.0574
Gnomad4 EAS
AF:
0.0624
Gnomad4 SAS
AF:
0.133
Gnomad4 FIN
AF:
0.0579
Gnomad4 NFE
AF:
0.0902
Gnomad4 OTH
AF:
0.128
Alfa
AF:
0.0998
Hom.:
809
Bravo
AF:
0.123
TwinsUK
AF:
0.0939
AC:
348
ALSPAC
AF:
0.102
AC:
394
ESP6500AA
AF:
0.177
AC:
535
ESP6500EA
AF:
0.0866
AC:
469
ExAC
AF:
0.0977
AC:
11498
Asia WGS
AF:
0.154
AC:
534
AN:
3478
EpiCase
AF:
0.0864
EpiControl
AF:
0.0878

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:17
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 28, 2016Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Macular degeneration Benign:3
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxNov 10, 2018This variant is associated with the following publications: (PMID: 28173125, 16518403, 19255449, 21555552, 16936732, 23112567, 18806293) -
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Atypical hemolytic-uremic syndrome Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
BF*FA/S Benign:1
Benign, no assertion criteria providedliterature onlyOMIMOct 30, 2017- -
Complement component 2 deficiency Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Complement component 2 deficiency;C3809653:Age related macular degeneration 14 Benign:1
Benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 22, 2022- -
Age related macular degeneration 14 Benign:1
protective, no assertion criteria providedliterature onlyOMIMAug 12, 2016- -
Focal segmental glomerulosclerosis Benign:1
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenSep 27, 2022- -
Atypical hemolytic-uremic syndrome with B factor anomaly Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Factor B fast/slow polymorphism Benign:1
Benign, no assertion criteria providedliterature onlyOMIMJan 01, 1994- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.064
BayesDel_addAF
Benign
-0.58
T
BayesDel_noAF
Benign
-0.46
Cadd
Benign
0.036
Dann
Benign
0.58
Eigen
Benign
-2.4
Eigen_PC
Benign
-2.4
FATHMM_MKL
Benign
0.046
N
LIST_S2
Benign
0.45
T;T;T
MetaRNN
Benign
0.0013
T;T;T
MetaSVM
Benign
-0.99
T
MutationTaster
Benign
1.0
P;P
PrimateAI
Benign
0.19
T
PROVEAN
Benign
0.49
N;N;N
REVEL
Benign
0.066
Sift
Benign
0.70
T;T;T
Sift4G
Benign
0.31
T;T;T
Polyphen
0.0050
.;.;B
Vest4
0.033
MPC
0.54
ClinPred
0.0030
T
GERP RS
-10
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.018
gMVP
0.45

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: rs641153; hg19: chr6-31914180; COSMIC: COSV54959257; COSMIC: COSV54959257; API