rs35186399

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001928.4(CFD):c.205G>A(p.Glu69Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00886 in 1,565,868 control chromosomes in the GnomAD database, including 84 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0066 ( 11 hom., cov: 31)

Exomes 𝑓: 0.0091 ( 73 hom. )

Consequence

CFD
NM_001928.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.65

Publications

13 publications found

Variant links:

Genes affected

CFD (HGNC:2771): (complement factor D) This gene encodes a member of the S1, or chymotrypsin, family of serine peptidases. This protease catalyzes the cleavage of factor B, the rate-limiting step of the alternative pathway of complement activation. This protein also functions as an adipokine, a cell signaling protein secreted by adipocytes, which regulates insulin secretion in mice. Mutations in this gene underlie complement factor D deficiency, which is associated with recurrent bacterial meningitis infections in human patients. Alternative splicing of this gene results in multiple transcript variants. At least one of these variants encodes a preproprotein that is proteolytically processed to generate the mature protease. [provided by RefSeq, Nov 2015]

CFD Gene-Disease associations (from GenCC):

recurrent Neisseria infections due to factor D deficiency
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

CFD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.004876882).

BP6

Variant 19-860766-G-A is Benign according to our data. Variant chr19-860766-G-A is described in ClinVar as Benign. ClinVar VariationId is 1165412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00659 (1001/152006) while in subpopulation NFE AF = 0.0101 (687/67884). AF 95% confidence interval is 0.00949. There are 11 homozygotes in GnomAd4. There are 469 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFD	NM_001928.4 link	c.205G>A	p.Glu69Lys	missense_variant	Exon 2 of 5	ENST00000327726.11	NP_001919.2	P00746
CFD	NM_001317335.2 link	c.226G>A	p.Glu76Lys	missense_variant	Exon 2 of 5		NP_001304264.1	P00746K7ERG9A6XNE2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFD	ENST00000327726.11 link	c.205G>A	p.Glu69Lys	missense_variant	Exon 2 of 5	1	NM_001928.4	ENSP00000332139.4		P00746

Frequencies

GnomAD3 genomes

AF:

0.00659

AC:

1001

AN:

151890

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00210

Gnomad AMI

AF:

0.0747

Gnomad AMR

AF:

0.00269

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00982

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0101

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00538

AC:

923

AN:

171718

AF XY:

0.00545

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00317

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00839

Gnomad NFE exome

AF:

0.0100

Gnomad OTH exome

AF:

0.00817

GnomAD4 exome

AF:

0.00911

AC:

12879

AN:

1413862

Hom.:

Cov.:

AF XY:

0.00876

AC XY:

6143

AN XY:

700986

show subpopulations

African (AFR)

AF:

0.00138

AC:

AN:

32514

American (AMR)

AF:

0.00149

AC:

AN:

40158

Ashkenazi Jewish (ASJ)

AF:

0.00295

AC:

AN:

25426

East Asian (EAS)

AF:

0.00

AC:

AN:

37650

South Asian (SAS)

AF:

0.000267

AC:

AN:

82486

European-Finnish (FIN)

AF:

0.00857

AC:

305

AN:

35572

Middle Eastern (MID)

AF:

0.00186

AC:

AN:

4298

European-Non Finnish (NFE)

AF:

0.0110

AC:

12016

AN:

1096940

Other (OTH)

AF:

0.00592

AC:

348

AN:

58818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

835

1670

2504

3339

4174

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

454

908

1362

1816

2270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00659

AC:

1001

AN:

152006

Hom.:

Cov.:

AF XY:

0.00631

AC XY:

469

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.00210

AC:

AN:

41488

American (AMR)

AF:

0.00268

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00982

AC:

104

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0101

AC:

687

AN:

67884

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

104

155

207

259

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00681

Hom.:

Bravo

AF:

0.00626

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00135

AC:

ESP6500EA

AF:

0.00756

AC:

ExAC

AF:

0.00475

AC:

526

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CFD: BS1, BS2 -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

CFD-related disorder

Benign:1

May 23, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.32

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.40

T;T

MetaRNN

Benign

0.0049

T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

-0.43

N;.

PhyloP100

1.6

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.96

N;.

REVEL

Benign

0.20

Sift

Benign

0.24

T;.

Sift4G

Benign

0.84

T;T

Polyphen

0.14

B;.

Vest4

0.36

MVP

0.72

MPC

0.34

ClinPred

0.0064

GERP RS

2.6

Varity_R

0.49

gMVP

0.66

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over