chr6-31948042-C-G

Position:

• chr6-31948042-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001710.6(CFB):​c.858C>G​(p.Phe286Leu) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars). Synonymous variant affecting the same amino acid position (i.e. F286F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFB NM_001710.6 missense
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 0.962

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]

ENSG00000244255 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFB	NM_001710.6	c.858C>G	p.Phe286Leu	missense_variant	6/18	ENST00000425368.7	NP_001701.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFB	ENST00000425368.7	c.858C>G	p.Phe286Leu	missense_variant	6/18	1	NM_001710.6	ENSP00000416561.2
ENSG00000244255	ENST00000456570.5	c.2364C>G	p.Phe788Leu	missense_variant	18/30	2		ENSP00000410815.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Atypical hemolytic-uremic syndrome with B factor anomaly Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jan 02, 2007

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	.;.;D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Pathogenic	2.9	.;.;M
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.70
MutPred		0.90		Loss of ubiquitination at K792 (P = 0.0896);.;.;
MVP		0.70
MPC		1.5
ClinPred		1.0	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.90

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

Other links and lift over

dbSNP: rs117905900; hg19: chr6-31915819;