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GeneBe

X-47624394-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001145252.3(CFP):c.1291T>G(p.Phe431Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000414 in 1,207,903 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000091 ( 0 hom., 0 hem., cov: 21)
Exomes 𝑓: 0.0000036 ( 0 hom. 1 hem. )

Consequence

CFP
NM_001145252.3 missense

Scores

4
8
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.33
Variant links:
Genes affected
CFP (HGNC:8864): (complement factor properdin) This gene encodes a plasma glycoprotein that positively regulates the alternative complement pathway of the innate immune system. This protein binds to many microbial surfaces and apoptotic cells and stabilizes the C3- and C5-convertase enzyme complexes in a feedback loop that ultimately leads to formation of the membrane attack complex and lysis of the target cell. Mutations in this gene result in two forms of properdin deficiency, which results in high susceptibility to meningococcal infections. Multiple alternatively spliced variants, encoding the same protein, have been identified.[provided by RefSeq, Feb 2009]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CFPNM_001145252.3 linkuse as main transcriptc.1291T>G p.Phe431Val missense_variant 9/9 ENST00000396992.8
CFPNM_002621.2 linkuse as main transcriptc.1291T>G p.Phe431Val missense_variant 10/10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CFPENST00000396992.8 linkuse as main transcriptc.1291T>G p.Phe431Val missense_variant 9/91 NM_001145252.3 P1
CFPENST00000247153.7 linkuse as main transcriptc.1291T>G p.Phe431Val missense_variant 10/105 P1
CFPENST00000478222.1 linkuse as main transcriptn.412T>G non_coding_transcript_exon_variant 3/32
CFPENST00000640573.1 linkuse as main transcriptn.1529T>G non_coding_transcript_exon_variant 7/75

Frequencies

GnomAD3 genomes
AF:
0.00000911
AC:
1
AN:
109818
Hom.:
0
Cov.:
21
AF XY:
0.00
AC XY:
0
AN XY:
32078
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000970
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000164
AC:
3
AN:
183332
Hom.:
0
AF XY:
0.0000148
AC XY:
1
AN XY:
67770
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000109
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000364
AC:
4
AN:
1098085
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
1
AN XY:
363455
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000114
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000911
AC:
1
AN:
109818
Hom.:
0
Cov.:
21
AF XY:
0.00
AC XY:
0
AN XY:
32078
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000970
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 15, 2021The c.1291T>G (p.F431V) alteration is located in exon 10 (coding exon 9) of the CFP gene. This alteration results from a T to G substitution at nucleotide position 1291, causing the phenylalanine (F) at amino acid position 431 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeAug 22, 2023Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFP protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 2381972). This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 431 of the CFP protein (p.Phe431Val). This variant is present in population databases (rs752325590, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with CFP-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.65
BayesDel_addAF
Benign
-0.024
T
BayesDel_noAF
Uncertain
-0.080
Cadd
Uncertain
24
Dann
Uncertain
0.99
DEOGEN2
Benign
0.30
T;T
FATHMM_MKL
Uncertain
0.92
D
M_CAP
Pathogenic
0.43
D
MetaRNN
Uncertain
0.65
D;D
MetaSVM
Benign
-0.59
T
MutationAssessor
Uncertain
2.9
M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.56
T
PROVEAN
Uncertain
-2.7
D;D
REVEL
Uncertain
0.30
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
0.99
D;D
Vest4
0.57
MutPred
0.44
Gain of disorder (P = 0.0596);Gain of disorder (P = 0.0596);
MVP
0.28
MPC
1.9
ClinPred
0.87
D
GERP RS
5.5
Varity_R
0.89
gMVP
0.92

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

LitVar

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

Other links and lift over

dbSNP: rs752325590; hg19: chrX-47483793; API