rs641153

Positions:

Variant summary

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

The NM_001710.6(CFB):c.95G>A(p.Arg32Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0989 in 1,612,870 control chromosomes in the GnomAD database, including 8,814 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R32W) has been classified as Benign.

Frequency

Genomes: 𝑓 0.12 ( 1207 hom., cov: 31)

Exomes 𝑓: 0.097 ( 7607 hom. )

Consequence

CFB
NM_001710.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: -2.31

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001252532).

BP6

Variant 6-31946403-G-A is Benign according to our data. Variant chr6-31946403-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 16075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-31946403-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFB	NM_001710.6 linkuse as main transcript	c.95G>A	p.Arg32Gln	missense_variant	2/18	ENST00000425368.7	NP_001701.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFB	ENST00000425368.7 linkuse as main transcript	c.95G>A	p.Arg32Gln	missense_variant	2/18	1	NM_001710.6	ENSP00000416561	P1	P00751-1

Frequencies

GnomAD3 genomes

AF:

0.116

AC:

17666

AN:

152026

Hom.:

1209

Cov.:

show subpopulations

Gnomad AFR

AF:

0.190

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.100

Gnomad ASJ

AF:

0.0574

Gnomad EAS

AF:

0.0624

Gnomad SAS

AF:

0.134

Gnomad FIN

AF:

0.0579

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.0902

Gnomad OTH

AF:

0.129

GnomAD3 exomes

AF:

0.0960

AC:

23669

AN:

246556

Hom.:

1358

AF XY:

0.0987

AC XY:

13261

AN XY:

134396

show subpopulations

Gnomad AFR exome

AF:

0.191

Gnomad AMR exome

AF:

0.0702

Gnomad ASJ exome

AF:

0.0522

Gnomad EAS exome

AF:

0.0619

Gnomad SAS exome

AF:

0.156

Gnomad FIN exome

AF:

0.0635

Gnomad NFE exome

AF:

0.0902

Gnomad OTH exome

AF:

0.103

GnomAD4 exome

AF:

0.0971

AC:

141800

AN:

1460726

Hom.:

7607

Cov.:

AF XY:

0.0979

AC XY:

71130

AN XY:

726674

show subpopulations

Gnomad4 AFR exome

AF:

0.188

Gnomad4 AMR exome

AF:

0.0734

Gnomad4 ASJ exome

AF:

0.0555

Gnomad4 EAS exome

AF:

0.0736

Gnomad4 SAS exome

AF:

0.149

Gnomad4 FIN exome

AF:

0.0650

Gnomad4 NFE exome

AF:

0.0942

Gnomad4 OTH exome

AF:

0.108

GnomAD4 genome

AF:

0.116

AC:

17688

AN:

152144

Hom.:

1207

Cov.:

AF XY:

0.114

AC XY:

8486

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.191

Gnomad4 AMR

AF:

0.100

Gnomad4 ASJ

AF:

0.0574

Gnomad4 EAS

AF:

0.0624

Gnomad4 SAS

AF:

0.133

Gnomad4 FIN

AF:

0.0579

Gnomad4 NFE

AF:

0.0902

Gnomad4 OTH

AF:

0.128

Alfa

AF:

0.0998

Hom.:

809

Bravo

AF:

0.123

TwinsUK

AF:

0.0939

AC:

348

ALSPAC

AF:

0.102

AC:

394

ESP6500AA

AF:

0.177

AC:

535

ESP6500EA

AF:

0.0866

AC:

469

ExAC

AF:

0.0977

AC:

11498

Asia WGS

AF:

0.154

AC:

534

AN:

3478

EpiCase

AF:

0.0864

EpiControl

AF:

0.0878

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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: Frequency -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 28173125, 16518403, 19255449, 21555552, 16936732, 23112567, 18806293) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Macular degeneration

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Atypical hemolytic-uremic syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

BF*FA/S

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Oct 30, 2017

- -

Complement component 2 deficiency;C3809653:Age related macular degeneration 14

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 22, 2022

- -

Complement component 2 deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Age related macular degeneration 14

Benign:1

protective, no assertion criteria provided

literature only

OMIM

Aug 12, 2016

- -

Focal segmental glomerulosclerosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 27, 2022

- -

Atypical hemolytic-uremic syndrome with B factor anomaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Factor B fast/slow polymorphism

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jan 01, 1994

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.036

DANN

Benign

0.58

DEOGEN2

Benign

0.030

.;.;T

Eigen

Benign

-2.4

Eigen_PC

Benign

-2.4

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.45

T;T;T

MetaRNN

Benign

0.0013

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.55

.;.;N

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.19

PROVEAN

Benign

0.49

N;N;N

REVEL

Benign

0.066

Sift

Benign

0.70

T;T;T

Sift4G

Benign

0.31

T;T;T

Polyphen

0.0050

.;.;B

Vest4

0.033

MPC

0.54

ClinPred

0.0030

GERP RS

-10

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.018

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over