X-47624325-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2

The NM_001145252.3(CFP):c.1360C>G(p.Pro454Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000331 in 1,207,908 control chromosomes in the GnomAD database, including 1 homozygotes. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P454S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000034 ( 1 hom. 10 hem. )

Consequence

CFP
NM_001145252.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.08

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]

CFP links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2903846).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000337 (37/1098033) while in subpopulation MID AF= 0.00653 (27/4134). AF 95% confidence interval is 0.00461. There are 1 homozygotes in gnomad4_exome. There are 10 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFP	NM_001145252.3 linkuse as main transcript	c.1360C>G	p.Pro454Ala	missense_variant	9/9	ENST00000396992.8
CFP	NM_002621.2 linkuse as main transcript	c.1360C>G	p.Pro454Ala	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CFP	ENST00000396992.8 linkuse as main transcript	c.1360C>G	p.Pro454Ala	missense_variant	9/9	1	NM_001145252.3	P1
CFP	ENST00000247153.7 linkuse as main transcript	c.1360C>G	p.Pro454Ala	missense_variant	10/10	5		P1
CFP	ENST00000478222.1 linkuse as main transcript	n.481C>G		non_coding_transcript_exon_variant	3/3	2
CFP	ENST00000640573.1 linkuse as main transcript	n.1598C>G		non_coding_transcript_exon_variant	7/7	5

Frequencies

GnomAD3 genomes

AF:

0.0000364

AC:

AN:

109821

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32047

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0000190

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000218

AC:

AN:

183522

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

67950

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000366

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000337

AC:

AN:

1098033

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

363387

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000831

Gnomad4 OTH exome

AF:

0.0000651

GnomAD4 genome

AF:

0.0000273

AC:

AN:

109875

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32111

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000190

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

CFP-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 10, 2023

The CFP c.1360C>G variant is predicted to result in the amino acid substitution p.Pro454Ala. This variant occurs within the terminal exon, near the c-terminus. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0037% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including two hemizygous individuals (http://gnomad.broadinstitute.org/variant/X-47483724-G-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 22, 2023

This variant has not been reported in the literature in individuals affected with CFP-related conditions. This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 454 of the CFP protein (p.Pro454Ala). This variant is present in population databases (rs768994510, gnomAD 0.002%). ClinVar contains an entry for this variant (Variation ID: 1497624). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.49

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.22

T;T

FATHMM_MKL

Uncertain

0.81

M_CAP

Benign

0.010

MetaRNN

Benign

0.29

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.8

M;M

MutationTaster

Benign

0.77

N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.059

Sift

Benign

0.23

T;T

Sift4G

Uncertain

0.034

D;D

Polyphen

0.58

P;P

Vest4

0.31

MutPred

0.43

Loss of catalytic residue at P454 (P = 0.01);Loss of catalytic residue at P454 (P = 0.01);

MVP

0.16

MPC

0.88

ClinPred

0.28

GERP RS

4.7

Varity_R

0.21

gMVP

0.69

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over