rs641153

Variant names:

• chr6-31946403-G-A
• rs641153
• NM_001710.6:c.95G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-31946403-G-A
• chr6-31946403-G-C
• chr6-31946403-G-T

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.95G>A​(p.Arg32Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0989 in 1,612,870 control chromosomes in the GnomAD database, including 8,814 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R32L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.12 (1207 hom., cov: 31)
  • Exomes 𝑓: 0.097 (7607 hom.)
• Consequence: CFB NM_001710.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: -2.31
• Publications: 226 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), Ambry Genetics, ClinGen
• complement factor b deficiency

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ENSG00000244255 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.001252532).
• BP6: Variant 6-31946403-G-A is Benign according to our data. Variant chr6-31946403-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 16075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.187 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFB	NM_001710.6	MANE Select	c.95G>A	p.Arg32Gln	missense	Exon 2 of 18	NP_001701.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFB	ENST00000425368.7	TSL:1 MANE Select	c.95G>A	p.Arg32Gln	missense	Exon 2 of 18	ENSP00000416561.2
	ENSG00000244255	ENST00000456570.5	TSL:2	c.1601G>A	p.Arg534Gln	missense	Exon 14 of 30	ENSP00000410815.1
	CFB	ENST00000885733.1		c.95G>A	p.Arg32Gln	missense	Exon 2 of 18	ENSP00000555792.1

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17666 AN: 152026 Hom.: 1209 Cov.: 31

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.0574

Gnomad EAS AF: 0.0624

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.0579

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0902

Gnomad OTH AF: 0.129

GnomAD2 exomes AF: 0.0960 AC: 23669 AN: 246556 AF XY: 0.0987

Gnomad AFR exome AF: 0.191

Gnomad AMR exome AF: 0.0702

Gnomad ASJ exome AF: 0.0522

Gnomad EAS exome AF: 0.0619

Gnomad FIN exome AF: 0.0635

Gnomad NFE exome AF: 0.0902

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.0971 AC: 141800 AN: 1460726 Hom.: 7607 Cov.: 34 AF XY: 0.0979 AC XY: 71130 AN XY: 726674

African (AFR) AF: 0.188 AC: 6288 AN: 33480

American (AMR) AF: 0.0734 AC: 3283 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0555 AC: 1451 AN: 26136

East Asian (EAS) AF: 0.0736 AC: 2923 AN: 39700

South Asian (SAS) AF: 0.149 AC: 12841 AN: 86258

European-Finnish (FIN) AF: 0.0650 AC: 3402 AN: 52310

Middle Eastern (MID) AF: 0.0688 AC: 397 AN: 5768

European-Non Finnish (NFE) AF: 0.0942 AC: 104704 AN: 1111972

Other (OTH) AF: 0.108 AC: 6511 AN: 60382

GnomAD4 genome AF: 0.116 AC: 17688 AN: 152144 Hom.: 1207 Cov.: 31 AF XY: 0.114 AC XY: 8486 AN XY: 74382

African (AFR) AF: 0.191 AC: 7907 AN: 41482

American (AMR) AF: 0.100 AC: 1531 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0574 AC: 199 AN: 3466

East Asian (EAS) AF: 0.0624 AC: 322 AN: 5162

South Asian (SAS) AF: 0.133 AC: 642 AN: 4824

European-Finnish (FIN) AF: 0.0579 AC: 614 AN: 10600

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0902 AC: 6132 AN: 68002

Other (OTH) AF: 0.128 AC: 271 AN: 2110

Alfa AF: 0.0999 Hom.: 1336

Bravo AF: 0.123

TwinsUK AF: 0.0939 AC: 348

ALSPAC AF: 0.102 AC: 394

ESP6500AA AF: 0.177 AC: 535

ESP6500EA AF: 0.0866 AC: 469

ExAC AF: 0.0977 AC: 11498

Asia WGS AF: 0.154 AC: 534 AN: 3478

EpiCase AF: 0.0864

EpiControl AF: 0.0878

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Atypical hemolytic-uremic syndrome (3)
-	-	3	Macular degeneration (3)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Atypical hemolytic-uremic syndrome with B factor anomaly (1)
-	-	1	BF*FA/S (1)
-	-	1	Complement component 2 deficiency (1)
-	-	1	Complement component 2 deficiency;C3809653:Age related macular degeneration 14 (1)
-	-	1	Factor B fast/slow polymorphism (1)
-	-	1	Focal segmental glomerulosclerosis (1)
-	-	-	Age related macular degeneration 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.036
DANN	Benign	0.58
DEOGEN2	Benign	0.030	T
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.55	N
PhyloP100		-2.3
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.49	N
REVEL	Benign	0.066
Sift	Benign	0.70	T
Sift4G	Benign	0.31	T
Polyphen		0.0050	B
Vest4		0.033
MPC		0.54
ClinPred		0.0030	T
GERP RS		-10
PromoterAI		-0.052	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.018
gMVP		0.45
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs641153; hg19: chr6-31914180; COSMIC: COSV54959257; COSMIC: COSV54959257;