NM_001710.6:c.1693A>G

Variant names:

• chr6-31950687-A-G
• rs4151659
• NM_001710.6:c.1693A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001710.6(CFB):​c.1693A>G​(p.Lys565Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,613,060 control chromosomes in the GnomAD database, including 218 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (45 hom., cov: 32)
  • Exomes 𝑓: 0.012 (173 hom.)
• Consequence: CFB NM_001710.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.905
• Publications: 31 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: 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

ENSG00000244255 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025326014).
• BP6: Variant 6-31950687-A-G is Benign according to our data. Variant chr6-31950687-A-G is described in ClinVar as Benign. ClinVar VariationId is 356292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0177 (2699/152294) while in subpopulation AFR AF = 0.0343 (1424/41546). AF 95% confidence interval is 0.0328. There are 45 homozygotes in GnomAd4. There are 1254 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 45 Unknown,AD,AR gene

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.1693A>G	p.Lys565Glu	missense	Exon 13 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.1693A>G	p.Lys565Glu	missense	Exon 13 of 18	ENSP00000416561.2	P00751-1
	ENSG00000244255	ENST00000456570.5	TSL:2	c.3199A>G	p.Lys1067Glu	missense	Exon 25 of 30	ENSP00000410815.1	B4E1Z4
	ENSG00000244255	ENST00000477310.1	TSL:5	c.2746A>G	p.Lys916Glu	missense	Exon 23 of 28	ENSP00000418996.1	E7ETN3

Frequencies

GnomAD3 genomes AF: 0.0177 AC: 2697 AN: 152176 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.0344

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0232

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0119

Gnomad OTH AF: 0.0253

GnomAD2 exomes AF: 0.0107 AC: 2648 AN: 246550 AF XY: 0.00987

Gnomad AFR exome AF: 0.0336

Gnomad AMR exome AF: 0.0184

Gnomad ASJ exome AF: 0.0121

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.0138

GnomAD4 exome AF: 0.0119 AC: 17363 AN: 1460766 Hom.: 173 Cov.: 33 AF XY: 0.0113 AC XY: 8230 AN XY: 726696

African (AFR) AF: 0.0332 AC: 1111 AN: 33480

American (AMR) AF: 0.0192 AC: 860 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0111 AC: 291 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000499 AC: 43 AN: 86256

European-Finnish (FIN) AF: 0.00212 AC: 111 AN: 52308

Middle Eastern (MID) AF: 0.0101 AC: 58 AN: 5768

European-Non Finnish (NFE) AF: 0.0128 AC: 14226 AN: 1112008

Other (OTH) AF: 0.0110 AC: 663 AN: 60386

GnomAD4 genome AF: 0.0177 AC: 2699 AN: 152294 Hom.: 45 Cov.: 32 AF XY: 0.0168 AC XY: 1254 AN XY: 74464

African (AFR) AF: 0.0343 AC: 1424 AN: 41546

American (AMR) AF: 0.0232 AC: 355 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10620

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0119 AC: 812 AN: 68014

Other (OTH) AF: 0.0250 AC: 53 AN: 2116

Alfa AF: 0.0135 Hom.: 100

Bravo AF: 0.0200

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.0341 AC: 103

ESP6500EA AF: 0.0155 AC: 84

ExAC AF: 0.0106 AC: 1250

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0133

EpiControl AF: 0.0142

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Atypical hemolytic-uremic syndrome (2)
-	-	2	not provided (2)
-	-	1	Atypical hemolytic-uremic syndrome with B factor anomaly (1)
-	-	1	CFB-related disorder (1)
-	-	1	Macular degeneration (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.91
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.091
Sift	Benign	0.068	T
Sift4G	Benign	0.36	T
Polyphen		0.055	B
Vest4		0.15
MPC		0.74
ClinPred		0.084	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.63
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4151659; hg19: chr6-31918464;