dbSNP rs149101394: CFB:p.Lys533Thr (chr6-31950377-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001710.6(CFB):c.1598A>C(p.Lys533Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K533R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CFB
NM_001710.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.45

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

atypical hemolytic-uremic syndrome with B factor anomaly
Inheritance: Unknown, AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
complement factor b deficiency
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

CFB links:

ENSG00000244255 (HGNC:):

ENSG00000244255 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08145204).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFB	NM_001710.6 link	c.1598A>C	p.Lys533Thr	missense_variant	Exon 12 of 18	ENST00000425368.7	NP_001701.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFB	ENST00000425368.7 link	c.1598A>C	p.Lys533Thr	missense_variant	Exon 12 of 18	1	NM_001710.6	ENSP00000416561.2
ENSG00000244255	ENST00000456570.5 link	c.3104A>C	p.Lys1035Thr	missense_variant	Exon 24 of 30	2		ENSP00000410815.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460722

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726678

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52282

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111992

Other (OTH)

AF:

0.00

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.065

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.0

.;.;T

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.68

T;T;T

M_CAP

Benign

0.043

MetaRNN

Benign

0.081

T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.0

.;.;N

PhyloP100

3.4

PrimateAI

Benign

0.28

PROVEAN

Benign

0.42

N;N;N

REVEL

Uncertain

0.29

Sift

Benign

0.26

T;T;T

Sift4G

Benign

0.54

T;T;T

Vest4

0.35

ClinPred

0.50

GERP RS

5.5

Varity_R

0.35

gMVP

0.66

Mutation Taster

=79/21

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over