rs45484591

Variant names:

• chr6-31950691-A-C
• rs45484591
• NM_001710.6:c.1697A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001710.6(CFB):​c.1697A>C​(p.Glu566Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,613,070 control chromosomes in the GnomAD database, including 225 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. E566K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0097 (12 hom., cov: 32)
  • Exomes 𝑓: 0.010 (213 hom.)
• Consequence: CFB NM_001710.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.657
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• atypical hemolytic-uremic syndrome with B factor anomaly

  Inheritance: AD, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• complement factor b deficiency

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• C3 glomerulonephritis

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000244255 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030397177).
• BP6: Variant 6-31950691-A-C is Benign according to our data. Variant chr6-31950691-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 225314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0933 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001710.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFB	NM_001710.6	MANE Select	c.1697A>C	p.Glu566Ala	missense	Exon 13 of 18	NP_001701.2	P00751-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFB	ENST00000425368.7	TSL:1 MANE Select	c.1697A>C	p.Glu566Ala	missense	Exon 13 of 18	ENSP00000416561.2	P00751-1
	ENSG00000244255	ENST00000456570.5	TSL:2	c.3203A>C	p.Glu1068Ala	missense	Exon 25 of 30	ENSP00000410815.1	B4E1Z4
	ENSG00000244255	ENST00000477310.1	TSL:5	c.2750A>C	p.Glu917Ala	missense	Exon 23 of 28	ENSP00000418996.1	E7ETN3

Frequencies

GnomAD3 genomes AF: 0.00968 AC: 1473 AN: 152186 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.00894

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.0111 AC: 2734 AN: 246556 AF XY: 0.0123

Gnomad AFR exome AF: 0.0113

Gnomad AMR exome AF: 0.00948

Gnomad ASJ exome AF: 0.0211

Gnomad EAS exome AF: 0.00126

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.0186

GnomAD4 exome AF: 0.0102 AC: 14965 AN: 1460766 Hom.: 213 Cov.: 33 AF XY: 0.0108 AC XY: 7870 AN XY: 726698

African (AFR) AF: 0.0102 AC: 343 AN: 33480

American (AMR) AF: 0.0103 AC: 459 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0226 AC: 590 AN: 26136

East Asian (EAS) AF: 0.00126 AC: 50 AN: 39700

South Asian (SAS) AF: 0.0246 AC: 2120 AN: 86256

European-Finnish (FIN) AF: 0.000899 AC: 47 AN: 52308

Middle Eastern (MID) AF: 0.100 AC: 577 AN: 5768

European-Non Finnish (NFE) AF: 0.00894 AC: 9937 AN: 1112008

Other (OTH) AF: 0.0139 AC: 842 AN: 60386

GnomAD4 genome AF: 0.00965 AC: 1470 AN: 152304 Hom.: 12 Cov.: 32 AF XY: 0.00971 AC XY: 723 AN XY: 74466

African (AFR) AF: 0.0103 AC: 427 AN: 41560

American (AMR) AF: 0.0122 AC: 187 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3472

East Asian (EAS) AF: 0.00231 AC: 12 AN: 5190

South Asian (SAS) AF: 0.0176 AC: 85 AN: 4828

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10620

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.00894 AC: 608 AN: 68020

Other (OTH) AF: 0.0227 AC: 48 AN: 2114

Alfa AF: 0.0103 Hom.: 50

Bravo AF: 0.0105

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00662 AC: 20

ESP6500EA AF: 0.00775 AC: 42

ExAC AF: 0.0110 AC: 1287

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.0118

EpiControl AF: 0.0125

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Atypical hemolytic-uremic syndrome (1)
-	-	1	Atypical hemolytic-uremic syndrome with B factor anomaly (1)
-	-	1	CFB-related disorder (1)
-	-	1	Complement component 2 deficiency (1)
-	-	1	Complement factor b deficiency (1)
-	-	1	Kidney disorder (1)
-	-	1	Macular degeneration (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	3.1
DANN	Benign	0.62
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.27	N
PhyloP100		-0.66
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.10
Sift	Benign	0.77	T
Sift4G	Benign	0.78	T
Polyphen		0.0	B
Vest4		0.064
MPC		0.50
ClinPred		0.0053	T
GERP RS		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.48
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs45484591; hg19: chr6-31918468; COSMIC: COSV64888616; COSMIC: COSV64888616;