rs4151667

Variant names:

• chr6-31946247-T-A
• rs4151667
• NM_001710.6:c.26T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 14/20 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:18
• Conservation: PhyloP100: 0.872
• Publications: 142 publications found

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

ENSG00000244255 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 16077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0505 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.26T>A	p.Leu9His	missense	Exon 1 of 18	NP_001701.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFB	ENST00000425368.7	TSL:1 MANE Select	c.26T>A	p.Leu9His	missense	Exon 1 of 18	ENSP00000416561.2
	ENSG00000244255	ENST00000456570.5	TSL:2	c.1571-126T>A		intron	N/A	ENSP00000410815.1
	CFB	ENST00000483004.2	TSL:5	c.26T>A	p.Leu9His	missense	Exon 1 of 16	ENSP00000419887.2

Frequencies

GnomAD3 genomes AF: 0.0339 AC: 5164 AN: 152182 Hom.: 107 Cov.: 32

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

GnomAD2 exomes AF: 0.0387 AC: 9547 AN: 246528 AF XY: 0.0405

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 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

African (AFR) AF: 0.0124 AC: 414 AN: 33480

American (AMR) AF: 0.0227 AC: 1016 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0257 AC: 671 AN: 26136

East Asian (EAS) AF: 0.0221 AC: 877 AN: 39700

South Asian (SAS) AF: 0.0517 AC: 4462 AN: 86258

European-Finnish (FIN) AF: 0.0550 AC: 2879 AN: 52324

Middle Eastern (MID) AF: 0.0270 AC: 156 AN: 5768

European-Non Finnish (NFE) AF: 0.0448 AC: 49856 AN: 1111986

Other (OTH) AF: 0.0383 AC: 2311 AN: 60386

GnomAD4 genome AF: 0.0339 AC: 5169 AN: 152300 Hom.: 108 Cov.: 32 AF XY: 0.0348 AC XY: 2591 AN XY: 74468

African (AFR) AF: 0.0123 AC: 512 AN: 41578

American (AMR) AF: 0.0253 AC: 387 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0251 AC: 87 AN: 3470

East Asian (EAS) AF: 0.0222 AC: 115 AN: 5174

South Asian (SAS) AF: 0.0553 AC: 267 AN: 4828

European-Finnish (FIN) AF: 0.0553 AC: 587 AN: 10618

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0460 AC: 3130 AN: 68012

Other (OTH) AF: 0.0307 AC: 65 AN: 2114

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:1 Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Jun 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 16518403, 16936732)

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Atypical hemolytic-uremic syndrome Benign:3

Sep 26, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

CFB p.Leu9His (c.26T>A) is a missense variant that changes the amino acid at residue 9 from Leucine to Histidine. This variant is present at high allele frequency in population databases. In conclusion, we classify CFB p.Leu9His (c.26T>A) as a benign variant.

Sep 02, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

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

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

Age related macular degeneration 14 Pathogenic:1

Sep 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Atypical hemolytic-uremic syndrome with B factor anomaly;C3809653:Age related macular degeneration 14;C3809950:Complement factor b deficiency Benign:1

Apr 25, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFB-related disorder Benign:1

Jul 26, 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

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). 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 v4.9

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
DEOGEN2	Benign	0.075	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0049	T
MetaSVM	Uncertain	-0.0028	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.87
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.16
MPC		1.1
ClinPred		0.026	T
GERP RS		5.3
PromoterAI		0.013	Neutral
Varity_R		0.24
gMVP		0.66
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

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