rs45484591

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001710.6(CFB):c.1697A>C(p.Glu566Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,613,070 control chromosomes in the GnomAD database, including 225 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. E566K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0097 ( 12 hom., cov: 32)

Exomes 𝑓: 0.010 ( 213 hom. )

Consequence

CFB
NM_001710.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.657

Publications

19 publications found

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]

CFB Gene-Disease associations (from GenCC):

atypical hemolytic-uremic syndrome with B factor anomaly
Inheritance: Unknown, AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
complement factor b deficiency
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

CFB links:

ENSG00000244255 (HGNC:):

ENSG00000244255 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030397177).

BP6

Variant 6-31950691-A-C is Benign according to our data. Variant chr6-31950691-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 225314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0933 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFB	NM_001710.6 link	c.1697A>C	p.Glu566Ala	missense_variant	Exon 13 of 18	ENST00000425368.7	NP_001701.2	P00751-1A0A1U9X7H8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFB	ENST00000425368.7 link	c.1697A>C	p.Glu566Ala	missense_variant	Exon 13 of 18	1	NM_001710.6	ENSP00000416561.2		P00751-1
ENSG00000244255	ENST00000456570.5 link	c.3203A>C	p.Glu1068Ala	missense_variant	Exon 25 of 30	2		ENSP00000410815.1		B4E1Z4

Frequencies

GnomAD3 genomes

AF:

0.00968

AC:

1473

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0102

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0122

Gnomad ASJ

AF:

0.0216

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.0178

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.00894

Gnomad OTH

AF:

0.0234

GnomAD2 exomes

AF:

0.0111

AC:

2734

AN:

246556

AF XY:

0.0123

show subpopulations

Gnomad AFR exome

AF:

0.0113

Gnomad AMR exome

AF:

0.00948

Gnomad ASJ exome

AF:

0.0211

Gnomad EAS exome

AF:

0.00126

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.0101

Gnomad OTH exome

AF:

0.0186

GnomAD4 exome

AF:

0.0102

AC:

14965

AN:

1460766

Hom.:

213

Cov.:

AF XY:

0.0108

AC XY:

7870

AN XY:

726698

show subpopulations

African (AFR)

AF:

0.0102

AC:

343

AN:

33480

American (AMR)

AF:

0.0103

AC:

459

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0226

AC:

590

AN:

26136

East Asian (EAS)

AF:

0.00126

AC:

AN:

39700

South Asian (SAS)

AF:

0.0246

AC:

2120

AN:

86256

European-Finnish (FIN)

AF:

0.000899

AC:

AN:

52308

Middle Eastern (MID)

AF:

0.100

AC:

577

AN:

5768

European-Non Finnish (NFE)

AF:

0.00894

AC:

9937

AN:

1112008

Other (OTH)

AF:

0.0139

AC:

842

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

986

1972

2958

3944

4930

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

386

772

1158

1544

1930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00965

AC:

1470

AN:

152304

Hom.:

Cov.:

AF XY:

0.00971

AC XY:

723

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0103

AC:

427

AN:

41560

American (AMR)

AF:

0.0122

AC:

187

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0216

AC:

AN:

3472

East Asian (EAS)

AF:

0.00231

AC:

AN:

5190

South Asian (SAS)

AF:

0.0176

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00894

AC:

608

AN:

68020

Other (OTH)

AF:

0.0227

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

152

227

303

379

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0103

Hom.:

Bravo

AF:

0.0105

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00882

AC:

ESP6500AA

AF:

0.00662

AC:

ESP6500EA

AF:

0.00775

AC:

ExAC

AF:

0.0110

AC:

1287

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.0118

EpiControl

AF:

0.0125

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CFB: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Complement factor b deficiency

Benign:1

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:reference population

- -

Kidney disorder

Benign:1

Feb 06, 2017

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Complement component 2 deficiency

Benign:1

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CFB-related disorder

Benign:1

Apr 02, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This 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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Macular degeneration

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.51

CADD

Benign

3.1

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.24

.;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.47

T;T;T

MetaRNN

Benign

0.0030

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.27

.;.;N

PhyloP100

-0.66

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.2

N;N;N

REVEL

Benign

0.10

Sift

Benign

0.77

T;T;T

Sift4G

Benign

0.78

T;T;T

Polyphen

0.0

.;.;B

Vest4

0.064

MPC

0.50

ClinPred

0.0053

GERP RS

-1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.17

gMVP

0.48

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over