6-31948042-C-T

Variant names:

• chr6-31948042-C-T
• rs117905900
• NM_001710.6:c.858C>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.858C>T​(p.Phe286Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 1,614,186 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (125 hom.)
• Consequence: CFB NM_001710.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.962
• Publications: 22 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=-0.53).
• BP6: Variant 6-31948042-C-T is Benign according to our data. Variant chr6-31948042-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 356281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.962 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00311 (473/152292) while in subpopulation EAS AF = 0.033 (171/5180). AF 95% confidence interval is 0.029. There are 7 homozygotes in GnomAd4. There are 243 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFB	NM_001710.6	MANE Select	c.858C>T	p.Phe286Phe	synonymous	Exon 6 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.858C>T	p.Phe286Phe	synonymous	Exon 6 of 18	ENSP00000416561.2
	ENSG00000244255	ENST00000456570.5	TSL:2	c.2364C>T	p.Phe788Phe	synonymous	Exon 18 of 30	ENSP00000410815.1
	ENSG00000244255	ENST00000477310.1	TSL:5	c.1911C>T	p.Phe637Phe	synonymous	Exon 16 of 28	ENSP00000418996.1

Frequencies

GnomAD3 genomes AF: 0.00311 AC: 473 AN: 152174 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0189

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0329

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.0108 AC: 2716 AN: 251446 AF XY: 0.00823

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0555

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0407

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.00254 AC: 3710 AN: 1461894 Hom.: 125 Cov.: 34 AF XY: 0.00219 AC XY: 1590 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0466 AC: 2082 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0363 AC: 1441 AN: 39700

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1112012

Other (OTH) AF: 0.00250 AC: 151 AN: 60396

GnomAD4 genome AF: 0.00311 AC: 473 AN: 152292 Hom.: 7 Cov.: 32 AF XY: 0.00326 AC XY: 243 AN XY: 74454

African (AFR) AF: 0.0000481 AC: 2 AN: 41570

American (AMR) AF: 0.0188 AC: 287 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0330 AC: 171 AN: 5180

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00120 Hom.: 4

Bravo AF: 0.00513

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Atypical hemolytic-uremic syndrome (2)
-	-	2	Macular degeneration (2)
-	-	1	Atypical hemolytic-uremic syndrome with B factor anomaly (1)
-	-	1	Complement component 2 deficiency (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	10
DANN	Benign	0.65
PhyloP100		0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs117905900; hg19: chr6-31915819;