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GeneBe

rs4151667

Variant summary

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

The NM_001710.6(CFB):c.26T>A(p.Leu9His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.042 in 1,613,062 control chromosomes in the GnomAD database, including 1,538 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.034 ( 108 hom., cov: 32)
Exomes 𝑓: 0.043 ( 1430 hom. )

Consequence

CFB
NM_001710.6 missense

Scores

2
2
11

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:16

Conservation

PhyloP100: 0.872
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=0.004921347).
BP6
Variant 6-31946247-T-A is Benign according to our data. Variant chr6-31946247-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 16077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-31946247-T-A is described in Lovd as [Likely_benign]. Variant chr6-31946247-T-A is described in Lovd as [Benign].
BA1
GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0505 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CFBNM_001710.6 linkuse as main transcriptc.26T>A p.Leu9His missense_variant 1/18 ENST00000425368.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CFBENST00000425368.7 linkuse as main transcriptc.26T>A p.Leu9His missense_variant 1/181 NM_001710.6 P1P00751-1

Frequencies

GnomAD3 genomes
AF:
0.0339
AC:
5164
AN:
152182
Hom.:
107
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0123
Gnomad AMI
AF:
0.0132
Gnomad AMR
AF:
0.0249
Gnomad ASJ
AF:
0.0251
Gnomad EAS
AF:
0.0220
Gnomad SAS
AF:
0.0559
Gnomad FIN
AF:
0.0553
Gnomad MID
AF:
0.0222
Gnomad NFE
AF:
0.0460
Gnomad OTH
AF:
0.0311
GnomAD3 exomes
AF:
0.0387
AC:
9547
AN:
246528
Hom.:
226
AF XY:
0.0405
AC XY:
5439
AN XY:
134376
show subpopulations
Gnomad AFR exome
AF:
0.0115
Gnomad AMR exome
AF:
0.0218
Gnomad ASJ exome
AF:
0.0248
Gnomad EAS exome
AF:
0.0181
Gnomad SAS exome
AF:
0.0527
Gnomad FIN exome
AF:
0.0550
Gnomad NFE exome
AF:
0.0454
Gnomad OTH exome
AF:
0.0374
GnomAD4 exome
AF:
0.0429
AC:
62642
AN:
1460762
Hom.:
1430
Cov.:
32
AF XY:
0.0435
AC XY:
31579
AN XY:
726696
show subpopulations
Gnomad4 AFR exome
AF:
0.0124
Gnomad4 AMR exome
AF:
0.0227
Gnomad4 ASJ exome
AF:
0.0257
Gnomad4 EAS exome
AF:
0.0221
Gnomad4 SAS exome
AF:
0.0517
Gnomad4 FIN exome
AF:
0.0550
Gnomad4 NFE exome
AF:
0.0448
Gnomad4 OTH exome
AF:
0.0383
GnomAD4 genome
AF:
0.0339
AC:
5169
AN:
152300
Hom.:
108
Cov.:
32
AF XY:
0.0348
AC XY:
2591
AN XY:
74468
show subpopulations
Gnomad4 AFR
AF:
0.0123
Gnomad4 AMR
AF:
0.0253
Gnomad4 ASJ
AF:
0.0251
Gnomad4 EAS
AF:
0.0222
Gnomad4 SAS
AF:
0.0553
Gnomad4 FIN
AF:
0.0553
Gnomad4 NFE
AF:
0.0460
Gnomad4 OTH
AF:
0.0307
Alfa
AF:
0.0362
Hom.:
91
Bravo
AF:
0.0292
TwinsUK
AF:
0.0440
AC:
163
ALSPAC
AF:
0.0368
AC:
142
ESP6500AA
AF:
0.00993
AC:
30
ESP6500EA
AF:
0.0423
AC:
229
ExAC
AF:
0.0386
AC:
4575
Asia WGS
AF:
0.0400
AC:
138
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Pathogenic:1Benign:16
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
Benign, criteria provided, single submitterclinical testingInvitaeJan 29, 2024- -
Likely benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingGeneDxJun 10, 2021This variant is associated with the following publications: (PMID: 16518403, 16936732) -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
not specified Benign:3
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: MAF -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Complement component 2 deficiency Benign:2
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Atypical hemolytic-uremic syndrome Benign:2
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenSep 02, 2022- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Macular degeneration Benign:2
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Age related macular degeneration 14 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 01, 2006- -
Atypical hemolytic-uremic syndrome with B factor anomaly;C3809653:Age related macular degeneration 14;C3809950:Complement factor b deficiency Benign:1
Benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 25, 2022- -
CFB-related condition Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJul 26, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Atypical hemolytic-uremic syndrome with B factor anomaly Benign:1
Likely 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.17
Cadd
Benign
20
Dann
Benign
0.84
Eigen
Benign
0.13
Eigen_PC
Benign
0.13
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.37
T;T
MetaRNN
Benign
0.0049
T;T
MetaSVM
Uncertain
-0.0028
T
MutationTaster
Benign
1.0
D;N
PROVEAN
Benign
-1.2
N;N
REVEL
Benign
0.17
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
.;D
Vest4
0.16
MPC
1.1
ClinPred
0.026
T
GERP RS
5.3
Varity_R
0.24
gMVP
0.66

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: rs4151667; hg19: chr6-31914024; COSMIC: COSV54962334; COSMIC: COSV54962334; API