rs121909748

Variant names:

• chr6-31948443-A-G
• rs121909748
• NM_001710.6:c.967A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM2 PM5 PP5_Moderate BP4

The NM_001710.6(CFB):​c.967A>G​(p.Lys323Glu) variant causes a missense 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. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K323Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFB NM_001710.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 0.559
• Publications: 23 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: Unknown, AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-31948443-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4280398.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 6-31948443-A-G is Pathogenic according to our data. Variant chr6-31948443-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 16080.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3449356). . Strength limited to SUPPORTING due to the PP5.

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.967A>G	p.Lys323Glu	missense	Exon 7 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.967A>G	p.Lys323Glu	missense	Exon 7 of 18	ENSP00000416561.2	P00751-1
	ENSG00000244255	ENST00000456570.5	TSL:2	c.2473A>G	p.Lys825Glu	missense	Exon 19 of 30	ENSP00000410815.1	B4E1Z4
	ENSG00000244255	ENST00000477310.1	TSL:5	c.2020A>G	p.Lys674Glu	missense	Exon 17 of 28	ENSP00000418996.1	E7ETN3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Atypical hemolytic-uremic syndrome (1)
-	-	-	Atypical hemolytic-uremic syndrome with B factor anomaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	10
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.56
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.34	N
REVEL	Uncertain	0.50
Sift	Benign	0.077	T
Sift4G	Benign	0.43	T
Polyphen		0.069	B
Vest4		0.67
MutPred		0.74		Loss of methylation at K825 (P = 0.0041)
MVP		0.26
MPC		0.71
ClinPred		0.51	D
GERP RS		3.1
Varity_R		0.27
gMVP		0.64
Mutation Taster		=32/68	disease causing

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

Other links and lift over

dbSNP: rs121909748; hg19: chr6-31916220;