6-31950377-A-G

Position:

chr6-31950377-A-G

Variant summary

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

The NM_001710.6(CFB):c.1598A>G(p.Lys533Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0048 in 1,613,030 control chromosomes in the GnomAD database, including 259 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 (★★).

Frequency

Genomes: 𝑓 0.0061 ( 25 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 234 hom. )

Consequence

CFB
NM_001710.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 3.45

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=0.0019727945).

BP6

Variant 6-31950377-A-G is Benign according to our data. Variant chr6-31950377-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 225313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-31950377-A-G is described in UniProt as null. Variant chr6-31950377-A-G is described in UniProt as null. Variant chr6-31950377-A-G is described in UniProt as null. Variant chr6-31950377-A-G is described in UniProt as null. Variant chr6-31950377-A-G is described in UniProt as null. Variant chr6-31950377-A-G is described in UniProt as null. Variant chr6-31950377-A-G is described in UniProt as null. Variant chr6-31950377-A-G is described in UniProt as null. Variant chr6-31950377-A-G is described in UniProt as null. Variant chr6-31950377-A-G is described in UniProt as null. Variant chr6-31950377-A-G is described in Lovd as [Likely_benign]. Variant chr6-31950377-A-G is described in Lovd as [Likely_pathogenic].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0706 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.1598A>G	p.Lys533Arg	missense_variant	12/18	ENST00000425368.7	NP_001701.2	P00751-1A0A1U9X7H8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFB	ENST00000425368.7 linkuse as main transcript	c.1598A>G	p.Lys533Arg	missense_variant	12/18	1	NM_001710.6	ENSP00000416561.2		P00751-1
ENSG00000244255	ENST00000456570.5 linkuse as main transcript	c.3104A>G	p.Lys1035Arg	missense_variant	24/30	2		ENSP00000410815.1		B4E1Z4

Frequencies

GnomAD3 genomes

AF:

0.00612

AC:

931

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0102

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00693

Gnomad SAS

AF:

0.0774

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000720

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00908

AC:

2242

AN:

247020

Hom.:

AF XY:

0.0115

AC XY:

1549

AN XY:

134570

show subpopulations

Gnomad AFR exome

AF:

0.0111

Gnomad AMR exome

AF:

0.00171

Gnomad ASJ exome

AF:

0.000401

Gnomad EAS exome

AF:

0.0106

Gnomad SAS exome

AF:

0.0556

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000820

Gnomad OTH exome

AF:

0.00592

GnomAD4 exome

AF:

0.00467

AC:

6817

AN:

1460720

Hom.:

234

Cov.:

AF XY:

0.00630

AC XY:

4581

AN XY:

726676

show subpopulations

Gnomad4 AFR exome

AF:

0.0114

Gnomad4 AMR exome

AF:

0.00152

Gnomad4 ASJ exome

AF:

0.000421

Gnomad4 EAS exome

AF:

0.00617

Gnomad4 SAS exome

AF:

0.0591

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000494

Gnomad4 OTH exome

AF:

0.00710

GnomAD4 genome

AF:

0.00611

AC:

930

AN:

152310

Hom.:

Cov.:

AF XY:

0.00733

AC XY:

546

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0102

Gnomad4 AMR

AF:

0.00255

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00714

Gnomad4 SAS

AF:

0.0770

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000720

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00182

Hom.:

Bravo

AF:

0.00475

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.0119

AC:

ESP6500EA

AF:

0.000185

AC:

ExAC

AF:

0.0103

AC:

1229

Asia WGS

AF:

0.0330

AC:

113

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.00160

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2021	This variant is associated with the following publications: (PMID: 20108004, 26911616, 33213850, 28939980, 28710236, 24652797, 30046676, 33238263, 27884173, 20513133) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 09, 2017	- -

Complement component 2 deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely 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	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jun 24, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

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	- -

not specified

Benign:1

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 5.8% in South Asian chr in ExAC. -

Complement factor b deficiency

Benign:1

Likely benign, criteria provided, single submitter

reference population

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Mar 18, 2016

- -

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 07, 2022

- -

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). 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 determine 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

0.086

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

0.020

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.14

.;.;T

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.75

T;T;T

MetaRNN

Benign

0.0020

T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.81

.;.;L

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.42

N;N;N

REVEL

Uncertain

0.49

Sift

Benign

0.24

T;T;T

Sift4G

Benign

0.48

T;T;T

Polyphen

0.0090

.;.;B

Vest4

0.70

MPC

0.38

ClinPred

0.030

GERP RS

5.5

Varity_R

0.25

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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