rs132630260

Variant names:

• chrX-47627290-G-C
• rs132630260
• NM_001145252.3:c.617C>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001145252.3(CFP):​c.617C>G​(p.Ser206*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000183 in 1,092,119 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: CFP NM_001145252.3 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.36
• Publications: 3 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-47627290-G-C is Pathogenic according to our data. Variant chrX-47627290-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 11184.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFP	NM_001145252.3	MANE Select	c.617C>G	p.Ser206*	stop_gained	Exon 5 of 9	NP_001138724.1	P27918
	CFP	NM_002621.2		c.617C>G	p.Ser206*	stop_gained	Exon 6 of 10	NP_002612.1	A0A0S2Z4I5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFP	ENST00000396992.8	TSL:1 MANE Select	c.617C>G	p.Ser206*	stop_gained	Exon 5 of 9	ENSP00000380189.3	P27918
	CFP	ENST00000377005.6	TSL:1	c.617C>G	p.Ser206*	stop_gained	Exon 5 of 8	ENSP00000366204.2	E9PAQ1
	CFP	ENST00000247153.7	TSL:5	c.617C>G	p.Ser206*	stop_gained	Exon 6 of 10	ENSP00000247153.3	P27918

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1092119 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 358141

African (AFR) AF: 0.00 AC: 0 AN: 26321

American (AMR) AF: 0.00 AC: 0 AN: 34720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19149

East Asian (EAS) AF: 0.00 AC: 0 AN: 30036

South Asian (SAS) AF: 0.00 AC: 0 AN: 53274

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4117

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 838587

Other (OTH) AF: 0.00 AC: 0 AN: 45773

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Properdin deficiency, X-linked (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	35
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		4.4
Vest4		0.86
GERP RS		5.4
Mutation Taster		=4/196	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: rs132630260; hg19: chrX-47486689;