rs4151650

Variant names:

• chr6-31947113-C-T
• rs4151650
• NM_001710.6:c.405C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001710.6(CFB):​c.405C>T​(p.Tyr135Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,613,052 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (30 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (17 hom.)
• Consequence: CFB NM_001710.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.260
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 6-31947113-C-T is Benign according to our data. Variant chr6-31947113-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 356271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.26 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.011 (1677/152284) while in subpopulation AFR AF = 0.0349 (1448/41546). AF 95% confidence interval is 0.0334. There are 30 homozygotes in GnomAd4. There are 814 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 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.405C>T	p.Tyr135Tyr	synonymous	Exon 3 of 18	NP_001701.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFB	ENST00000425368.7	TSL:1 MANE Select	c.405C>T	p.Tyr135Tyr	synonymous	Exon 3 of 18	ENSP00000416561.2
	ENSG00000244255	ENST00000456570.5	TSL:2	c.1911C>T	p.Tyr637Tyr	synonymous	Exon 15 of 30	ENSP00000410815.1
	ENSG00000244255	ENST00000477310.1	TSL:5	c.1458C>T	p.Tyr486Tyr	synonymous	Exon 13 of 28	ENSP00000418996.1

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1673 AN: 152166 Hom.: 30 Cov.: 31

Gnomad AFR AF: 0.0348

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00811

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000999

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00360 AC: 887 AN: 246608 AF XY: 0.00264

Gnomad AFR exome AF: 0.0342

Gnomad AMR exome AF: 0.00638

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.000219

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00109

Gnomad OTH exome AF: 0.00280

GnomAD4 exome AF: 0.00157 AC: 2292 AN: 1460768 Hom.: 17 Cov.: 30 AF XY: 0.00144 AC XY: 1043 AN XY: 726700

African (AFR) AF: 0.0288 AC: 963 AN: 33480

American (AMR) AF: 0.00644 AC: 288 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39700

South Asian (SAS) AF: 0.000301 AC: 26 AN: 86258

European-Finnish (FIN) AF: 0.000268 AC: 14 AN: 52310

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.000692 AC: 770 AN: 1112006

Other (OTH) AF: 0.00333 AC: 201 AN: 60386

GnomAD4 genome AF: 0.0110 AC: 1677 AN: 152284 Hom.: 30 Cov.: 31 AF XY: 0.0109 AC XY: 814 AN XY: 74456

African (AFR) AF: 0.0349 AC: 1448 AN: 41546

American (AMR) AF: 0.00810 AC: 124 AN: 15302

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

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00100 AC: 68 AN: 68028

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.00729 Hom.: 19

Bravo AF: 0.0125

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.00160

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	7.3
DANN	Benign	0.87
PhyloP100		0.26
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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: rs4151650; hg19: chr6-31914890;