chr6-31950377-A-G

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.1598A>G(p.Lys533Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0048 in 1,613,030 control chromosomes in the GnomAD database, including 259 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0061 ( 25 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 234 hom. )

Consequence

CFB
NM_001710.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 3.45

Publications

24 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=0.0019727945).

BP6

Variant 6-31950377-A-G is Benign according to our data. Variant chr6-31950377-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 225313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0706 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001710.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFB	NM_001710.6	MANE Select	c.1598A>G	p.Lys533Arg	missense	Exon 12 of 18	NP_001701.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CFB	ENST00000425368.7	TSL:1 MANE Select	c.1598A>G	p.Lys533Arg	missense	Exon 12 of 18	ENSP00000416561.2
ENSG00000244255	ENST00000456570.5	TSL:2	c.3104A>G	p.Lys1035Arg	missense	Exon 24 of 30	ENSP00000410815.1
ENSG00000244255	ENST00000477310.1	TSL:5	c.2651A>G	p.Lys884Arg	missense	Exon 22 of 28	ENSP00000418996.1

Frequencies

GnomAD3 genomes

AF:

0.00612

AC:

931

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0102

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00693

Gnomad SAS

AF:

0.0774

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000720

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00908

AC:

2242

AN:

247020

AF XY:

0.0115

show subpopulations

Gnomad AFR exome

AF:

0.0111

Gnomad AMR exome

AF:

0.00171

Gnomad ASJ exome

AF:

0.000401

Gnomad EAS exome

AF:

0.0106

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000820

Gnomad OTH exome

AF:

0.00592

GnomAD4 exome

AF:

0.00467

AC:

6817

AN:

1460720

Hom.:

234

Cov.:

AF XY:

0.00630

AC XY:

4581

AN XY:

726676

show subpopulations

African (AFR)

AF:

0.0114

AC:

381

AN:

33478

American (AMR)

AF:

0.00152

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000421

AC:

AN:

26136

East Asian (EAS)

AF:

0.00617

AC:

245

AN:

39700

South Asian (SAS)

AF:

0.0591

AC:

5102

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52282

Middle Eastern (MID)

AF:

0.00555

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000494

AC:

549

AN:

1111992

Other (OTH)

AF:

0.00710

AC:

429

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

492

984

1476

1968

2460

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

270

360

450

<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:

0.00611

AC:

930

AN:

152310

Hom.:

Cov.:

AF XY:

0.00733

AC XY:

546

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0102

AC:

423

AN:

41548

American (AMR)

AF:

0.00255

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00714

AC:

AN:

5180

South Asian (SAS)

AF:

0.0770

AC:

372

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000720

AC:

AN:

68032

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

140

186

233

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00249

Hom.:

Bravo

AF:

0.00475

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.0119

AC:

ESP6500EA

AF:

0.000185

AC:

ExAC

AF:

0.0103

AC:

1229

Asia WGS

AF:

0.0330

AC:

113

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.00160

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 09, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 22, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 20108004, 26911616, 33213850, 28939980, 28710236, 24652797, 30046676, 33238263, 27884173, 20513133)

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Atypical hemolytic-uremic syndrome

Benign:3

Jun 24, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 26, 2025

Genomenon, Inc, Genomenon, Inc

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

CFB p.Lys533Arg (c.1598A>G) is a missense variant that changes the amino acid at residue 533 from Lysine to Arginine. This variant is present at high allele frequency in population databases. In conclusion, we classify CFB p.Lys533Arg (c.1598A>G) as a benign variant.

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Complement component 2 deficiency

Benign:2

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Macular degeneration

Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant 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 5.8% in South Asian chr in ExAC.

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

Atypical hemolytic-uremic syndrome with B factor anomaly;C3809653:Age related macular degeneration 14;C3809950:Complement factor b deficiency

Benign:1

Apr 07, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Atypical hemolytic-uremic syndrome with B factor anomaly

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

0.020

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.14

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0020

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.81

PhyloP100

3.4

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.42

REVEL

Uncertain

0.49

Sift

Benign

0.24

Sift4G

Benign

0.48

Polyphen

0.0090

Vest4

0.70

MPC

0.38

ClinPred

0.030

GERP RS

5.5

Varity_R

0.25

gMVP

0.54

Mutation Taster

=90/10

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over