6-31946402-C-T

Position:

chr6-31946402-C-T

Variant summary

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

The NM_001710.6(CFB):c.94C>T(p.Arg32Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,612,892 control chromosomes in the GnomAD database, including 13,042 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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. R32Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.17 ( 3028 hom., cov: 32)

Exomes 𝑓: 0.10 ( 10014 hom. )

Consequence

CFB
NM_001710.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.787

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=0.005584061).

BP6

Variant 6-31946402-C-T is Benign according to our data. Variant chr6-31946402-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 16076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-31946402-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.325 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFB	NM_001710.6 linkuse as main transcript	c.94C>T	p.Arg32Trp	missense_variant	2/18	ENST00000425368.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFB	ENST00000425368.7 linkuse as main transcript	c.94C>T	p.Arg32Trp	missense_variant	2/18	1	NM_001710.6	P1	P00751-1

Frequencies

GnomAD3 genomes

AF:

0.170

AC:

25908

AN:

152038

Hom.:

3019

Cov.:

show subpopulations

Gnomad AFR

AF:

0.329

Gnomad AMI

AF:

0.0899

Gnomad AMR

AF:

0.145

Gnomad ASJ

AF:

0.0897

Gnomad EAS

AF:

0.0612

Gnomad SAS

AF:

0.189

Gnomad FIN

AF:

0.167

Gnomad MID

AF:

0.196

Gnomad NFE

AF:

0.0923

Gnomad OTH

AF:

0.172

GnomAD3 exomes

AF:

0.124

AC:

30666

AN:

246544

Hom.:

2613

AF XY:

0.127

AC XY:

17133

AN XY:

134392

show subpopulations

Gnomad AFR exome

AF:

0.333

Gnomad AMR exome

AF:

0.0877

Gnomad ASJ exome

AF:

0.0913

Gnomad EAS exome

AF:

0.0605

Gnomad SAS exome

AF:

0.204

Gnomad FIN exome

AF:

0.156

Gnomad NFE exome

AF:

0.0929

Gnomad OTH exome

AF:

0.120

GnomAD4 exome

AF:

0.103

AC:

149734

AN:

1460736

Hom.:

10014

Cov.:

AF XY:

0.106

AC XY:

76903

AN XY:

726684

show subpopulations

Gnomad4 AFR exome

AF:

0.341

Gnomad4 AMR exome

AF:

0.0955

Gnomad4 ASJ exome

AF:

0.0939

Gnomad4 EAS exome

AF:

0.0695

Gnomad4 SAS exome

AF:

0.204

Gnomad4 FIN exome

AF:

0.152

Gnomad4 NFE exome

AF:

0.0860

Gnomad4 OTH exome

AF:

0.108

GnomAD4 genome

AF:

0.171

AC:

25960

AN:

152156

Hom.:

3028

Cov.:

AF XY:

0.174

AC XY:

12949

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.329

Gnomad4 AMR

AF:

0.145

Gnomad4 ASJ

AF:

0.0897

Gnomad4 EAS

AF:

0.0612

Gnomad4 SAS

AF:

0.190

Gnomad4 FIN

AF:

0.167

Gnomad4 NFE

AF:

0.0923

Gnomad4 OTH

AF:

0.169

Alfa

AF:

0.102

Hom.:

1859

Bravo

AF:

0.175

TwinsUK

AF:

0.0823

AC:

305

ALSPAC

AF:

0.0921

AC:

355

ESP6500AA

AF:

0.319

AC:

964

ESP6500EA

AF:

0.0978

AC:

530

ExAC

AF:

0.131

AC:

15354

Asia WGS

AF:

0.125

AC:

437

AN:

3478

EpiCase

AF:

0.0966

EpiControl

AF:

0.0993

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Macular degeneration

Benign:4

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

Complement component 2 deficiency

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	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 21541267, 19255449, 19009711, 28173125, 33334325) -

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	- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 09, 2022

- -

CFB-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 02, 2019

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

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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Focal segmental glomerulosclerosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 27, 2022

- -

Factor B fast/slow polymorphism

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Oct 28, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.041

.;.;T

Eigen

Benign

-0.96

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.51

T;T;T

MetaRNN

Benign

0.0056

T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

0.55

.;.;N

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.19

PROVEAN

Benign

-1.2

N;N;N

REVEL

Benign

0.28

Sift

Benign

0.033

D;D;D

Sift4G

Uncertain

0.013

D;D;D

Polyphen

0.98

.;.;D

Vest4

0.079

MPC

0.86

ClinPred

0.039

GERP RS

-4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.044

gMVP

0.60

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

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