X-47624325-G-A

Position:

• chrX-47624325-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001145252.3(CFP):​c.1360C>T​(p.Pro454Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000031 in 1,098,033 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 18 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000031 (0 hom. 18 hem.)
• Consequence: CFP NM_001145252.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.08

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23581174).
• BS2: High Hemizygotes in GnomAdExome4 at 18 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFP	NM_001145252.3	c.1360C>T	p.Pro454Ser	missense_variant	9/9	ENST00000396992.8	NP_001138724.1
CFP	NM_002621.2	c.1360C>T	p.Pro454Ser	missense_variant	10/10		NP_002612.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFP	ENST00000396992.8	c.1360C>T	p.Pro454Ser	missense_variant	9/9	1	NM_001145252.3	ENSP00000380189.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000545 AC: 1 AN: 183522 Hom.: 0 AF XY: 0.0000147 AC XY: 1 AN XY: 67950

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: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000310 AC: 34 AN: 1098033 Hom.: 0 Cov.: 30 AF XY: 0.0000495 AC XY: 18 AN XY: 363387

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.000108

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000756

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2024

The c.1360C>T (p.P454S) alteration is located in exon 10 (coding exon 9) of the CFP gene. This alteration results from a C to T substitution at nucleotide position 1360, causing the proline (P) at amino acid position 454 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 02, 2022

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with CFP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 454 of the CFP protein (p.Pro454Ser). 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	0.098
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;T
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.69	.;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.028
Sift	Benign	0.093	T;T
Sift4G	Benign	0.076	T;T
Polyphen		0.079	B;B
Vest4		0.19
MutPred		0.36		Loss of catalytic residue at P454 (P = 0.0111);Loss of catalytic residue at P454 (P = 0.0111);
MVP		0.082
MPC		0.80
ClinPred		0.58	D
GERP RS		4.7
Varity_R		0.25
gMVP		0.72

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

Other links and lift over

dbSNP: rs768994510; hg19: chrX-47483724;