rs761962858

chrX-47628269-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001145252.3(CFP):c.236G>A(p.Arg79Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000553 in 1,206,119 control chromosomes in the GnomAD database, including 4 homozygotes. There are 354 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., 10 hem., cov: 23)
  • Exomes 𝑓: 0.00059 (4 hom. 344 hem.)
• Consequence: CFP NM_001145252.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.25

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0075173676).
• BP6: Variant X-47628269-C-T is Benign according to our data. Variant chrX-47628269-C-T is described in ClinVar as [Benign]. Clinvar id is 235395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-47628269-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000206 (23/111864) while in subpopulation SAS AF= 0.00782 (21/2687). AF 95% confidence interval is 0.00524. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFP	NM_001145252.3	c.236G>A	p.Arg79Gln	missense_variant	3/9	ENST00000396992.8
CFP	NM_002621.2	c.236G>A	p.Arg79Gln	missense_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFP	ENST00000396992.8	c.236G>A	p.Arg79Gln	missense_variant	3/9	1	NM_001145252.3	P1

Frequencies

GnomAD3 genomes AF: 0.000206 AC: 23 AN: 111812 Hom.: 0 Cov.: 23 AF XY: 0.000294 AC XY: 10 AN XY: 33974

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000281

Gnomad SAS AF: 0.00779

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00114 AC: 195 AN: 170702 Hom.: 0 AF XY: 0.00161 AC XY: 93 AN XY: 57724

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000152

Gnomad SAS exome AF: 0.00990

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000148

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.000589 AC: 644 AN: 1094255 Hom.: 4 Cov.: 31 AF XY: 0.000955 AC XY: 344 AN XY: 360023

Gnomad4 AFR exome AF: 0.0000380

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000998

Gnomad4 SAS exome AF: 0.00983

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000929

Gnomad4 OTH exome AF: 0.000718

GnomAD4 genome AF: 0.000206 AC: 23 AN: 111864 Hom.: 0 Cov.: 23 AF XY: 0.000294 AC XY: 10 AN XY: 34036

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000282

Gnomad4 SAS AF: 0.00782

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000127 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.00145 AC: 176

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 30, 2015	- -

CFP-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.0080
Dann	Benign	0.75
DEOGEN2	Benign	0.13	T;T;T
FATHMM_MKL	Benign	0.0059	N
MetaRNN	Benign	0.0075	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.42	N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.38	N;N;N
REVEL	Benign	0.027
Sift	Benign	0.53	T;T;T
Sift4G	Benign	0.55	T;T;T
Polyphen		0.0040	B;B;.
Vest4		0.062
MutPred		0.50		Loss of MoRF binding (P = 0.0454);Loss of MoRF binding (P = 0.0454);Loss of MoRF binding (P = 0.0454);
MVP		0.10
MPC		0.74
ClinPred		0.0043	T
GERP RS		-5.6
Varity_R		0.091
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs761962858; hg19: chrX-47487668; COSMIC: COSV55949624; COSMIC: COSV55949624;