rs4151651

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001710.6(CFB):c.754G>A(p.Gly252Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0313 in 1,613,848 control chromosomes in the GnomAD database, including 962 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 48 hom., cov: 32)

Exomes 𝑓: 0.032 ( 914 hom. )

Consequence

CFB
NM_001710.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.08

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:

ENSG00000244255 (HGNC:):

ENSG00000244255 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=0.00227499).

BP6

Variant 6-31947837-G-A is Benign according to our data. Variant chr6-31947837-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 356280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-31947837-G-A is described in Lovd as [Benign]. Variant chr6-31947837-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0226 (3436/152252) while in subpopulation NFE AF= 0.0364 (2475/68018). AF 95% confidence interval is 0.0352. There are 48 homozygotes in gnomad4. There are 1588 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 48 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFB	NM_001710.6 link	c.754G>A	p.Gly252Ser	missense_variant	Exon 5 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.754G>A	p.Gly252Ser	missense_variant	Exon 5 of 18	1	NM_001710.6	ENSP00000416561.2		P00751-1
ENSG00000244255	ENST00000456570.5 link	c.2260G>A	p.Gly754Ser	missense_variant	Exon 17 of 30	2		ENSP00000410815.1		B4E1Z4

Frequencies

GnomAD3 genomes

AF:

0.0226

AC:

3437

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00729

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0163

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0268

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.0364

Gnomad OTH

AF:

0.0263

GnomAD3 exomes

AF:

0.0222

AC:

5559

AN:

250304

Hom.:

AF XY:

0.0220

AC XY:

2977

AN XY:

135556

show subpopulations

Gnomad AFR exome

AF:

0.00604

Gnomad AMR exome

AF:

0.0132

Gnomad ASJ exome

AF:

0.0132

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00212

Gnomad FIN exome

AF:

0.0250

Gnomad NFE exome

AF:

0.0362

Gnomad OTH exome

AF:

0.0278

GnomAD4 exome

AF:

0.0323

AC:

47155

AN:

1461596

Hom.:

914

Cov.:

AF XY:

0.0311

AC XY:

22634

AN XY:

727092

show subpopulations

Gnomad4 AFR exome

AF:

0.00496

Gnomad4 AMR exome

AF:

0.0133

Gnomad4 ASJ exome

AF:

0.0128

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.00235

Gnomad4 FIN exome

AF:

0.0293

Gnomad4 NFE exome

AF:

0.0382

Gnomad4 OTH exome

AF:

0.0308

GnomAD4 genome

AF:

0.0226

AC:

3436

AN:

152252

Hom.:

Cov.:

AF XY:

0.0213

AC XY:

1588

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00727

Gnomad4 AMR

AF:

0.0163

Gnomad4 ASJ

AF:

0.0112

Gnomad4 EAS

AF:

0.000966

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.0268

Gnomad4 NFE

AF:

0.0364

Gnomad4 OTH

AF:

0.0261

Alfa

AF:

0.0309

Hom.:

161

Bravo

AF:

0.0204

TwinsUK

AF:

0.0437

AC:

162

ALSPAC

AF:

0.0379

AC:

146

ESP6500AA

AF:

0.00893

AC:

ESP6500EA

AF:

0.0389

AC:

211

ExAC

AF:

0.0219

AC:

2654

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0304

EpiControl

AF:

0.0311

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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 -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

- -

Complement component 2 deficiency

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CFB-related disorder

Benign:1

Aug 05, 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

May 10, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

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

0.056

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.024

.;.;T

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.12

T;T;T

MetaRNN

Benign

0.0023

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.3

.;.;N

PrimateAI

Benign

0.35

PROVEAN

Benign

0.64

N;N;N

REVEL

Benign

0.17

Sift

Benign

0.88

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

.;.;B

Vest4

0.054

MPC

0.46

ClinPred

0.0064

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.036

gMVP

0.34

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

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