Genetic Variant CFD:p.Val213Ala (chr19-863114-T-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001317335.2(CFD):c.659T>C(p.Val220Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000727 in 1,374,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V220G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

CFD
NM_001317335.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.70

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.907

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001317335.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFD	NM_001928.4	MANE Select	c.638T>C	p.Val213Ala	missense	Exon 5 of 5	NP_001919.2
	CFD	NM_001317335.2		c.659T>C	p.Val220Ala	missense	Exon 5 of 5	NP_001304264.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CFD	ENST00000327726.11	TSL:1 MANE Select	c.638T>C	p.Val213Ala	missense	Exon 5 of 5	ENSP00000332139.4
CFD	ENST00000592860.3	TSL:1	c.659T>C	p.Val220Ala	missense	Exon 5 of 5	ENSP00000468253.1
CFD	ENST00000866187.1		c.638T>C	p.Val213Ala	missense	Exon 5 of 6	ENSP00000536246.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.27e-7

AC:

AN:

1374834

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

676462

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31360

American (AMR)

AF:

0.00

AC:

AN:

35490

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25044

East Asian (EAS)

AF:

0.00

AC:

AN:

35426

South Asian (SAS)

AF:

0.00

AC:

AN:

79018

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34254

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5386

European-Non Finnish (NFE)

AF:

9.33e-7

AC:

AN:

1071522

Other (OTH)

AF:

0.00

AC:

AN:

57334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.55

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

0.64

MutationAssessor

Benign

1.5

PhyloP100

3.7

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-2.9

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.55

MutPred

0.84

Gain of disorder (P = 0.0813)

MVP

0.86

MPC

0.98

ClinPred

0.97

GERP RS

4.3

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.8

Varity_R

0.78

gMVP

0.75

Mutation Taster

=44/56

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over