Genetic Variant CFD:p.Val213Gly (chr19-863114-T-G) – 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_001928.4(CFD):c.638T>G(p.Val213Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000145 in 1,374,834 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).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

CFD
NM_001928.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.70

Publications

4 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, 0.908

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001928.4. 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
	CFD	NM_001928.4	MANE Select	c.638T>G	p.Val213Gly	missense	Exon 5 of 5	NP_001919.2
	CFD	NM_001317335.2		c.659T>G	p.Val220Gly	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>G	p.Val213Gly	missense	Exon 5 of 5	ENSP00000332139.4
CFD	ENST00000592860.3	TSL:1	c.659T>G	p.Val220Gly	missense	Exon 5 of 5	ENSP00000468253.1
CFD	ENST00000695945.1		c.587T>G	p.Val196Gly	missense	Exon 5 of 5	ENSP00000512278.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000730

AC:

AN:

137030

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:

0.0000186

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1374834

Hom.:

Cov.:

AF XY:

0.00000148

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:

0.00000187

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

Uncertain

0.51

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.76

M_CAP

Pathogenic

0.75

MetaRNN

Pathogenic

0.91

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

3.2

PhyloP100

3.7

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-5.7

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.47

MutPred

0.81

Gain of disorder (P = 0.0146)

MVP

0.91

MPC

1.0

ClinPred

0.97

GERP RS

4.3

Varity_R

0.99

gMVP

0.91

Mutation Taster

=42/58

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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