6-31947837-G-T

Variant names:

• chr6-31947837-G-T
• rs4151651
• NM_001710.6:c.754G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001710.6(CFB):​c.754G>T​(p.Gly252Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. G252S) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CFB NM_001710.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17842323).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFB	NM_001710.6	c.754G>T	p.Gly252Cys	missense_variant	Exon 5 of 18	ENST00000425368.7	NP_001701.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFB	ENST00000425368.7	c.754G>T	p.Gly252Cys	missense_variant	Exon 5 of 18	1	NM_001710.6	ENSP00000416561.2
ENSG00000244255	ENST00000456570.5	c.2260G>T	p.Gly754Cys	missense_variant	Exon 17 of 30	2		ENSP00000410815.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250304 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135556

Gnomad AFR exome AF: 0.0000629

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74434

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.085	.;.;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.33	T;T;T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.34	.;.;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.20
Sift	Benign	0.050	D;D;D
Sift4G	Uncertain	0.037	D;D;T
Polyphen		0.31	.;.;B
Vest4		0.20
MutPred		0.32		Loss of disorder (P = 0.0713);.;.;
MVP		0.72
MPC		0.74
ClinPred		0.36	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4151651; hg19: chr6-31915614;