Genetic Variant CFP:p.Tyr414His (chrX-47626062-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM5BP4_Moderate

The NM_001145252.3(CFP):c.1240T>C(p.Tyr414His) variant causes a missense change. The variant allele was found at a frequency of 0.00000513 in 1,170,701 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y414D) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000019 ( 0 hom. 0 hem. )

Consequence

CFP
NM_001145252.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.29

Publications

8 publications found

Variant links:

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

CFP links:

ENSG00000283743 (HGNC:):

ENSG00000283743 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-47626062-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 11185.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.23068368).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFP	NM_001145252.3 link	c.1240T>C	p.Tyr414His	missense_variant	Exon 8 of 9	ENST00000396992.8	NP_001138724.1
CFP	NM_002621.2 link	c.1240T>C	p.Tyr414His	missense_variant	Exon 9 of 10		NP_002612.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFP	ENST00000396992.8 link	c.1240T>C	p.Tyr414His	missense_variant	Exon 8 of 9	1	NM_001145252.3	ENSP00000380189.3

Frequencies

GnomAD3 genomes

AF:

0.0000360

AC:

AN:

111088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000131

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000189

AC:

AN:

1059613

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

344781

show subpopulations

African (AFR)

AF:

0.0000785

AC:

AN:

25469

American (AMR)

AF:

0.00

AC:

AN:

28999

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18669

East Asian (EAS)

AF:

0.00

AC:

AN:

28118

South Asian (SAS)

AF:

0.00

AC:

AN:

50376

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38233

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4086

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

821066

Other (OTH)

AF:

0.00

AC:

AN:

44597

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000360

AC:

AN:

111088

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33294

show subpopulations

African (AFR)

AF:

0.000131

AC:

AN:

30444

American (AMR)

AF:

0.00

AC:

AN:

10502

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.00

AC:

AN:

3530

South Asian (SAS)

AF:

0.00

AC:

AN:

2612

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6017

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52924

Other (OTH)

AF:

0.00

AC:

AN:

1497

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000341

Hom.:

Bravo

AF:

0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;T;T

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.0

.;T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.23

T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Benign

1.5

L;L;.

PhyloP100

6.3

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.3

N;N;N

REVEL

Benign

0.22

Sift

Benign

0.13

T;T;T

Sift4G

Pathogenic

0.0

D;D;D

Vest4

0.28

ClinPred

0.83

GERP RS

5.5

Varity_R

0.35

gMVP

0.81

Mutation Taster

=71/29

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over