rs4151659

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001710.6(CFB):c.1693A>G(p.Lys565Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,613,060 control chromosomes in the GnomAD database, including 218 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 45 hom., cov: 32)

Exomes 𝑓: 0.012 ( 173 hom. )

Consequence

CFB
NM_001710.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.905

Publications

31 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=0.0025326014).

BP6

Variant 6-31950687-A-G is Benign according to our data. Variant chr6-31950687-A-G is described in ClinVar as Benign. ClinVar VariationId is 356292.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 = 0.0177 (2699/152294) while in subpopulation AFR AF = 0.0343 (1424/41546). AF 95% confidence interval is 0.0328. There are 45 homozygotes in GnomAd4. There are 1254 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 45 Unknown,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFB	NM_001710.6 link	c.1693A>G	p.Lys565Glu	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.1693A>G	p.Lys565Glu	missense_variant	Exon 13 of 18	1	NM_001710.6	ENSP00000416561.2		P00751-1
ENSG00000244255	ENST00000456570.5 link	c.3199A>G	p.Lys1067Glu	missense_variant	Exon 25 of 30	2		ENSP00000410815.1		B4E1Z4

Frequencies

GnomAD3 genomes

AF:

0.0177

AC:

2697

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0344

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0232

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0119

Gnomad OTH

AF:

0.0253

GnomAD2 exomes

AF:

0.0107

AC:

2648

AN:

246550

AF XY:

0.00987

show subpopulations

Gnomad AFR exome

AF:

0.0336

Gnomad AMR exome

AF:

0.0184

Gnomad ASJ exome

AF:

0.0121

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00166

Gnomad NFE exome

AF:

0.0113

Gnomad OTH exome

AF:

0.0138

GnomAD4 exome

AF:

0.0119

AC:

17363

AN:

1460766

Hom.:

173

Cov.:

AF XY:

0.0113

AC XY:

8230

AN XY:

726696

show subpopulations

African (AFR)

AF:

0.0332

AC:

1111

AN:

33480

American (AMR)

AF:

0.0192

AC:

860

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0111

AC:

291

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000499

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00212

AC:

111

AN:

52308

Middle Eastern (MID)

AF:

0.0101

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0128

AC:

14226

AN:

1112008

Other (OTH)

AF:

0.0110

AC:

663

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

1061

2122

3182

4243

5304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

578

1156

1734

2312

2890

<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:

0.0177

AC:

2699

AN:

152294

Hom.:

Cov.:

AF XY:

0.0168

AC XY:

1254

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0343

AC:

1424

AN:

41546

American (AMR)

AF:

0.0232

AC:

355

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000414

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0119

AC:

812

AN:

68014

Other (OTH)

AF:

0.0250

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

142

285

427

570

712

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0135

Hom.:

100

Bravo

AF:

0.0200

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.0341

AC:

103

ESP6500EA

AF:

0.0155

AC:

ExAC

AF:

0.0106

AC:

1250

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0133

EpiControl

AF:

0.0142

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CFB: BP4, BS1, BS2 -

CFB-related disorder

Benign:1

Apr 01, 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. -

Atypical hemolytic-uremic syndrome

Benign:1

Jul 08, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

0.13

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

.;.;T

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.51

T;T;T

MetaRNN

Benign

0.0025

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

.;.;L

PhyloP100

0.91

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.091

Sift

Benign

0.068

T;D;T

Sift4G

Benign

0.36

T;T;T

Polyphen

0.055

.;.;B

Vest4

0.15

MPC

0.74

ClinPred

0.084

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.53

gMVP

0.63

Mutation Taster

=93/7

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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