rs512559

Variant names:

• chr6-31948285-A-G
• rs512559
• NM_001710.6:c.898-89A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001710.6(CFB):​c.898-89A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0429 in 1,581,496 control chromosomes in the GnomAD database, including 1,906 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.050 (264 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1642 hom.)
• Consequence: CFB NM_001710.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0320
• Publications: 13 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 6-31948285-A-G is Benign according to our data. Variant chr6-31948285-A-G is described in ClinVar as Benign. ClinVar VariationId is 1279132.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0919 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFB	NM_001710.6	c.898-89A>G		intron_variant	Intron 6 of 17	ENST00000425368.7	NP_001701.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFB	ENST00000425368.7	c.898-89A>G		intron_variant	Intron 6 of 17	1	NM_001710.6	ENSP00000416561.2
ENSG00000244255	ENST00000456570.5	c.2404-89A>G		intron_variant	Intron 18 of 29	2		ENSP00000410815.1

Frequencies

GnomAD3 genomes AF: 0.0505 AC: 7677 AN: 152058 Hom.: 264 Cov.: 32

Gnomad AFR AF: 0.0945

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0519

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0404

Gnomad OTH AF: 0.0547

GnomAD4 exome AF: 0.0421 AC: 60215 AN: 1429320 Hom.: 1642 Cov.: 29 AF XY: 0.0401 AC XY: 28568 AN XY: 713034

African (AFR) AF: 0.0931 AC: 3056 AN: 32840

American (AMR) AF: 0.0383 AC: 1704 AN: 44474

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 345 AN: 25918

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39520

South Asian (SAS) AF: 0.000447 AC: 38 AN: 85040

European-Finnish (FIN) AF: 0.00494 AC: 261 AN: 52876

Middle Eastern (MID) AF: 0.00952 AC: 54 AN: 5670

European-Non Finnish (NFE) AF: 0.0483 AC: 52286 AN: 1083620

Other (OTH) AF: 0.0416 AC: 2469 AN: 59362

GnomAD4 genome AF: 0.0505 AC: 7684 AN: 152176 Hom.: 264 Cov.: 32 AF XY: 0.0475 AC XY: 3537 AN XY: 74416

African (AFR) AF: 0.0944 AC: 3916 AN: 41496

American (AMR) AF: 0.0519 AC: 793 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.00264 AC: 28 AN: 10606

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0404 AC: 2746 AN: 68004

Other (OTH) AF: 0.0541 AC: 114 AN: 2106

Alfa AF: 0.0425 Hom.: 509

Bravo AF: 0.0581

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.4
DANN	Benign	0.36
PhyloP100		-0.032
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs512559; hg19: chr6-31916062;