X-47624316-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001145252.3(CFP):c.1369C>T(p.His457Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,098,079 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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: 0.0000027 (0 hom. 0 hem.)
• Consequence: CFP NM_001145252.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4028728).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFP	NM_001145252.3	c.1369C>T	p.His457Tyr	missense_variant	9/9	ENST00000396992.8
CFP	NM_002621.2	c.1369C>T	p.His457Tyr	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFP	ENST00000396992.8	c.1369C>T	p.His457Tyr	missense_variant	9/9	1	NM_001145252.3	P1
CFP	ENST00000247153.7	c.1369C>T	p.His457Tyr	missense_variant	10/10	5		P1
CFP	ENST00000478222.1	n.490C>T		non_coding_transcript_exon_variant	3/3	2
CFP	ENST00000640573.1	n.1607C>T		non_coding_transcript_exon_variant	7/7	5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.0000109 AC: 2 AN: 183528 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67956

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: 0.0000244

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1098079 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363437

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: 0.00000356

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 07, 2023

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 457 of the CFP protein (p.His457Tyr). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with CFP-related conditions. ClinVar contains an entry for this variant (Variation ID: 1716976). 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 disruptive. 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	-0.19	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;T
FATHMM_MKL	Benign	0.63	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.40	T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	0.51	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.16
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.92	P;P
Vest4		0.38
MutPred		0.35		Gain of catalytic residue at H457 (P = 0.0876);Gain of catalytic residue at H457 (P = 0.0876);
MVP		0.30
MPC		1.5
ClinPred		0.85	D
GERP RS		4.7
Varity_R		0.71
gMVP		0.76

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: rs1367480015; hg19: chrX-47483715;