chrX-47626820-C-A

Variant names:

• chrX-47626820-C-A
• rs28935480
• NM_001145252.3:c.893G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001145252.3(CFP):​c.893G>T​(p.Gly298Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. G298G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 24)
• Consequence: CFP NM_001145252.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.91
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• properdin deficiency, X-linked

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000283743 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant X-47626820-C-A is Pathogenic according to our data. Variant chrX-47626820-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11183.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145252.3. 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
	CFP	NM_001145252.3	MANE Select	c.893G>T	p.Gly298Val	missense	Exon 6 of 9	NP_001138724.1
	CFP	NM_002621.2		c.893G>T	p.Gly298Val	missense	Exon 7 of 10	NP_002612.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFP	ENST00000396992.8	TSL:1 MANE Select	c.893G>T	p.Gly298Val	missense	Exon 6 of 9	ENSP00000380189.3
	CFP	ENST00000377005.6	TSL:1	c.893G>T	p.Gly298Val	missense	Exon 6 of 8	ENSP00000366204.2
	CFP	ENST00000247153.7	TSL:5	c.893G>T	p.Gly298Val	missense	Exon 7 of 10	ENSP00000247153.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Properdin deficiency, X-linked Pathogenic:1

Jul 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		5.9
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-8.6	D
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.82		Loss of disorder (P = 0.0494)
MVP		0.65
MPC		1.9
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.99
gMVP		0.95
Mutation Taster		=9/91	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs28935480; hg19: chrX-47486219;