6-31946247-T-A

Position:

chr6-31946247-T-A

Variant summary

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

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. 13/19 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:17

Conservation

PhyloP100: 0.872

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=0.004921347).

BP6

Variant 6-31946247-T-A is Benign according to our data. Variant chr6-31946247-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 16077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-31946247-T-A is described in Lovd as [Likely_benign]. Variant chr6-31946247-T-A is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0505 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.26T>A	p.Leu9His	missense_variant	1/18	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.26T>A	p.Leu9His	missense_variant	1/18	1	NM_001710.6	ENSP00000416561	P1	P00751-1

Frequencies

GnomAD3 genomes

AF:

0.0339

AC:

5164

AN:

152182

Hom.:

107

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0387

AC:

9547

AN:

246528

Hom.:

226

AF XY:

0.0405

AC XY:

5439

AN XY:

134376

show subpopulations

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 SAS exome

AF:

0.0527

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.:

AF XY:

0.0435

AC XY:

31579

AN XY:

726696

show subpopulations

Gnomad4 AFR exome

AF:

0.0124

Gnomad4 AMR exome

AF:

0.0227

Gnomad4 ASJ exome

AF:

0.0257

Gnomad4 EAS exome

AF:

0.0221

Gnomad4 SAS exome

AF:

0.0517

Gnomad4 FIN exome

AF:

0.0550

Gnomad4 NFE exome

AF:

0.0448

Gnomad4 OTH exome

AF:

0.0383

GnomAD4 genome

AF:

0.0339

AC:

5169

AN:

152300

Hom.:

108

Cov.:

AF XY:

0.0348

AC XY:

2591

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0123

Gnomad4 AMR

AF:

0.0253

Gnomad4 ASJ

AF:

0.0251

Gnomad4 EAS

AF:

0.0222

Gnomad4 SAS

AF:

0.0553

Gnomad4 FIN

AF:

0.0553

Gnomad4 NFE

AF:

0.0460

Gnomad4 OTH

AF:

0.0307

Alfa

AF:

0.0362

Hom.:

Bravo

AF:

0.0292

TwinsUK

AF:

0.0440

AC:

163

ALSPAC

AF:

0.0368

AC:

142

ESP6500AA

AF:

0.00993

AC:

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:1Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2021	This variant is associated with the following publications: (PMID: 16518403, 16936732) -

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: MAF -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Complement component 2 deficiency

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Atypical hemolytic-uremic syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Sep 02, 2022	- -

Macular degeneration

Benign:2

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

Age related macular degeneration 14

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2006

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 25, 2022

- -

CFB-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 26, 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

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.075

.;T

Eigen

Benign

0.13

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.37

T;T

MetaRNN

Benign

0.0049

T;T

MetaSVM

Uncertain

-0.0028

MutationAssessor

Benign

0.69

.;N

MutationTaster

Benign

1.0

D;N

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.17

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.16

MPC

1.1

ClinPred

0.026

GERP RS

5.3

Varity_R

0.24

gMVP

0.66

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