NM_001710.6:c.1598A>G

Variant names:

• chr6-31950377-A-G
• rs149101394
• NM_001710.6:c.1598A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001710.6(CFB):​c.1598A>G​(p.Lys533Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0048 in 1,613,030 control chromosomes in the GnomAD database, including 259 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (25 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (234 hom.)
• Consequence: CFB NM_001710.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 3.45
• Publications: 24 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=0.0019727945).
• BP6: Variant 6-31950377-A-G is Benign according to our data. Variant chr6-31950377-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 225313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0706 is higher than 0.05.

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.1598A>G	p.Lys533Arg	missense	Exon 12 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.1598A>G	p.Lys533Arg	missense	Exon 12 of 18	ENSP00000416561.2	P00751-1
	ENSG00000244255	ENST00000456570.5	TSL:2	c.3104A>G	p.Lys1035Arg	missense	Exon 24 of 30	ENSP00000410815.1	B4E1Z4
	ENSG00000244255	ENST00000477310.1	TSL:5	c.2651A>G	p.Lys884Arg	missense	Exon 22 of 28	ENSP00000418996.1	E7ETN3

Frequencies

GnomAD3 genomes AF: 0.00612 AC: 931 AN: 152192 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00693

Gnomad SAS AF: 0.0774

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00908 AC: 2242 AN: 247020 AF XY: 0.0115

Gnomad AFR exome AF: 0.0111

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.000401

Gnomad EAS exome AF: 0.0106

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000820

Gnomad OTH exome AF: 0.00592

GnomAD4 exome AF: 0.00467 AC: 6817 AN: 1460720 Hom.: 234 Cov.: 32 AF XY: 0.00630 AC XY: 4581 AN XY: 726676

African (AFR) AF: 0.0114 AC: 381 AN: 33478

American (AMR) AF: 0.00152 AC: 68 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000421 AC: 11 AN: 26136

East Asian (EAS) AF: 0.00617 AC: 245 AN: 39700

South Asian (SAS) AF: 0.0591 AC: 5102 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52282

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5768

European-Non Finnish (NFE) AF: 0.000494 AC: 549 AN: 1111992

Other (OTH) AF: 0.00710 AC: 429 AN: 60384

GnomAD4 genome AF: 0.00611 AC: 930 AN: 152310 Hom.: 25 Cov.: 32 AF XY: 0.00733 AC XY: 546 AN XY: 74478

African (AFR) AF: 0.0102 AC: 423 AN: 41548

American (AMR) AF: 0.00255 AC: 39 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00714 AC: 37 AN: 5180

South Asian (SAS) AF: 0.0770 AC: 372 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000720 AC: 49 AN: 68032

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00249 Hom.: 9

Bravo AF: 0.00475

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0119 AC: 36

ESP6500EA AF: 0.000185 AC: 1

ExAC AF: 0.0103 AC: 1229

Asia WGS AF: 0.0330 AC: 113 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.00160

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Atypical hemolytic-uremic syndrome (3)
-	-	2	Complement component 2 deficiency (2)
-	-	2	Macular degeneration (2)
-	-	1	Atypical hemolytic-uremic syndrome with B factor anomaly (1)
-	-	1	Atypical hemolytic-uremic syndrome with B factor anomaly;C3809653:Age related macular degeneration 14;C3809950:Complement factor b deficiency (1)
-	-	1	Complement factor b deficiency (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	20
DANN	Benign	0.90
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.81	L
PhyloP100		3.4
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.42	N
REVEL	Uncertain	0.49
Sift	Benign	0.24	T
Sift4G	Benign	0.48	T
Polyphen		0.0090	B
Vest4		0.70
MPC		0.38
ClinPred		0.030	T
GERP RS		5.5
Varity_R		0.25
gMVP		0.54
Mutation Taster		=90/10	polymorphism (auto)

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

Other links and lift over

dbSNP: rs149101394; hg19: chr6-31918154; COSMIC: COSV54961541; COSMIC: COSV54961541;