dbSNP rs267606721: CFD:p.Cys214Arg (chr19-863116-T-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001928.4(CFD):c.640T>C(p.Cys214Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000218 in 1,377,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as no classification for the single variant (no stars). Synonymous variant affecting the same amino acid position (i.e. C214C) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

CFD
NM_001928.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.69

Publications

5 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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFD	NM_001928.4 link	c.640T>C	p.Cys214Arg	missense_variant	Exon 5 of 5	ENST00000327726.11	NP_001919.2	P00746
CFD	NM_001317335.2 link	c.661T>C	p.Cys221Arg	missense_variant	Exon 5 of 5		NP_001304264.1	P00746K7ERG9A6XNE2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFD	ENST00000327726.11 link	c.640T>C	p.Cys214Arg	missense_variant	Exon 5 of 5	1	NM_001928.4	ENSP00000332139.4		P00746

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000728

AC:

AN:

137446

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000185

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000218

AC:

AN:

1377902

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

678736

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31424

American (AMR)

AF:

0.00

AC:

AN:

35534

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25082

East Asian (EAS)

AF:

0.00

AC:

AN:

35508

South Asian (SAS)

AF:

0.00

AC:

AN:

79066

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34296

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5432

European-Non Finnish (NFE)

AF:

0.00000279

AC:

AN:

1074050

Other (OTH)

AF:

0.00

AC:

AN:

57510

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.001311), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.000499

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

-0.084

MutationAssessor

Benign

1.7

L;.

PhyloP100

4.7

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-8.6

D;.

REVEL

Uncertain

0.49

Sift

Uncertain

0.0060

D;.

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.75

MutPred

0.93

Gain of disorder (P = 0.0156);.;

MVP

0.94

MPC

1.2

ClinPred

0.98

GERP RS

4.3

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.9

Varity_R

0.98

gMVP

0.94

Mutation Taster

=22/78

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over