6-31950687-A-G

Position:

chr6-31950687-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001710.6(CFB):c.1693A>G(p.Lys565Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,613,060 control chromosomes in the GnomAD database, including 218 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 45 hom., cov: 32)

Exomes 𝑓: 0.012 ( 173 hom. )

Consequence

CFB
NM_001710.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.905

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025326014).

BP6

Variant 6-31950687-A-G is Benign according to our data. Variant chr6-31950687-A-G is described in ClinVar as [Benign]. Clinvar id is 356292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-31950687-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0177 (2699/152294) while in subpopulation AFR AF= 0.0343 (1424/41546). AF 95% confidence interval is 0.0328. There are 45 homozygotes in gnomad4. There are 1254 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 45 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFB	NM_001710.6 linkuse as main transcript	c.1693A>G	p.Lys565Glu	missense_variant	13/18	ENST00000425368.7	NP_001701.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFB	ENST00000425368.7 linkuse as main transcript	c.1693A>G	p.Lys565Glu	missense_variant	13/18	1	NM_001710.6	ENSP00000416561	P1	P00751-1

Frequencies

GnomAD3 genomes

AF:

0.0177

AC:

2697

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0344

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0232

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0119

Gnomad OTH

AF:

0.0253

GnomAD3 exomes

AF:

0.0107

AC:

2648

AN:

246550

Hom.:

AF XY:

0.00987

AC XY:

1326

AN XY:

134412

show subpopulations

Gnomad AFR exome

AF:

0.0336

Gnomad AMR exome

AF:

0.0184

Gnomad ASJ exome

AF:

0.0121

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000461

Gnomad FIN exome

AF:

0.00166

Gnomad NFE exome

AF:

0.0113

Gnomad OTH exome

AF:

0.0138

GnomAD4 exome

AF:

0.0119

AC:

17363

AN:

1460766

Hom.:

173

Cov.:

AF XY:

0.0113

AC XY:

8230

AN XY:

726696

show subpopulations

Gnomad4 AFR exome

AF:

0.0332

Gnomad4 AMR exome

AF:

0.0192

Gnomad4 ASJ exome

AF:

0.0111

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000499

Gnomad4 FIN exome

AF:

0.00212

Gnomad4 NFE exome

AF:

0.0128

Gnomad4 OTH exome

AF:

0.0110

GnomAD4 genome

AF:

0.0177

AC:

2699

AN:

152294

Hom.:

Cov.:

AF XY:

0.0168

AC XY:

1254

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0343

Gnomad4 AMR

AF:

0.0232

Gnomad4 ASJ

AF:

0.0112

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.000659

Gnomad4 NFE

AF:

0.0119

Gnomad4 OTH

AF:

0.0250

Alfa

AF:

0.0131

Hom.:

Bravo

AF:

0.0200

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.0341

AC:

103

ESP6500EA

AF:

0.0155

AC:

ExAC

AF:

0.0106

AC:

1250

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0133

EpiControl

AF:

0.0142

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

CFB-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Atypical hemolytic-uremic syndrome with B factor anomaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Atypical hemolytic-uremic syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 08, 2022

- -

Macular degeneration

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

.;.;T

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.51

T;T;T

MetaRNN

Benign

0.0025

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

.;.;L

MutationTaster

Benign

0.82

D;N

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.091

Sift

Benign

0.068

T;D;T

Sift4G

Benign

0.36

T;T;T

Polyphen

0.055

.;.;B

Vest4

0.15

MPC

0.74

ClinPred

0.084

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.53

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over