Genetic Variant CFB:p.Gly21Ala (chr6-31946283-G-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.62G>C(p.Gly21Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/25 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. G21E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

CFB
NM_001710.6 missense, splice_region

Scores

Splicing: ADA: 0.00002399

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.450

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: 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

CFB links:

ENSG00000244255 (HGNC:):

ENSG00000244255 links:

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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=0.14335904).

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.62G>C	p.Gly21Ala	missense splice_region	Exon 1 of 18	NP_001701.2	P00751-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CFB	ENST00000425368.7	TSL:1 MANE Select	c.62G>C	p.Gly21Ala	missense splice_region	Exon 1 of 18	ENSP00000416561.2	P00751-1
ENSG00000244255	ENST00000456570.5	TSL:2	c.1571-90G>C		intron	N/A	ENSP00000410815.1	B4E1Z4
CFB	ENST00000885733.1		c.62G>C	p.Gly21Ala	missense splice_region	Exon 1 of 18	ENSP00000555792.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.091

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.023

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.61

M_CAP

Benign

0.018

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.69

PhyloP100

0.45

PROVEAN

Benign

0.19

REVEL

Benign

0.028

Sift

Benign

0.50

Sift4G

Benign

0.58

Polyphen

0.010

Vest4

0.085

MutPred

0.51

Loss of glycosylation at S20 (P = 0.0436)

MVP

0.70

MPC

0.51

ClinPred

0.16

GERP RS

2.4

PromoterAI

0.0063

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.034

gMVP

0.77

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000024

dbscSNV1_RF

Benign

0.020

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.22

Position offset: 3

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over