rs150103256

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000631.5(NCF4):c.478G>A(p.Val160Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,570,010 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 8 hom. )

Consequence

NCF4
NM_000631.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.0690

Publications

4 publications found

Variant links:

Genes affected

NCF4 (HGNC:7662): (neutrophil cytosolic factor 4) The protein encoded by this gene is a cytosolic regulatory component of the superoxide-producing phagocyte NADPH-oxidase, a multicomponent enzyme system important for host defense. This protein is preferentially expressed in cells of myeloid lineage. It interacts primarily with neutrophil cytosolic factor 2 (NCF2/p67-phox) to form a complex with neutrophil cytosolic factor 1 (NCF1/p47-phox), which further interacts with the small G protein RAC1 and translocates to the membrane upon cell stimulation. This complex then activates flavocytochrome b, the membrane-integrated catalytic core of the enzyme system. The PX domain of this protein can bind phospholipid products of the PI(3) kinase, which suggests its role in PI(3) kinase-mediated signaling events. The phosphorylation of this protein was found to negatively regulate the enzyme activity. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

NCF4 Gene-Disease associations (from GenCC):

granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
chronic granulomatous disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NCF4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003737539).

BP6

Variant 22-36871659-G-A is Benign according to our data. Variant chr22-36871659-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 341554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00123 (187/152366) while in subpopulation SAS AF = 0.0101 (49/4834). AF 95% confidence interval is 0.00788. There are 3 homozygotes in GnomAd4. There are 101 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCF4	NM_000631.5 link	c.478G>A	p.Val160Met	missense_variant	Exon 6 of 10	ENST00000248899.11	NP_000622.2	Q15080-1
NCF4	NM_013416.4 link	c.478G>A	p.Val160Met	missense_variant	Exon 6 of 9		NP_038202.2	Q15080-3
NCF4	XM_047441384.1 link	c.652G>A	p.Val218Met	missense_variant	Exon 7 of 11		XP_047297340.1
NCF4	XM_047441385.1 link	c.622G>A	p.Val208Met	missense_variant	Exon 7 of 11		XP_047297341.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCF4	ENST00000248899.11 link	c.478G>A	p.Val160Met	missense_variant	Exon 6 of 10	1	NM_000631.5	ENSP00000248899.6		Q15080-1

Frequencies

GnomAD3 genomes

AF:

0.00123

AC:

187

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00269

Gnomad SAS

AF:

0.0101

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000941

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00176

AC:

324

AN:

184276

AF XY:

0.00194

show subpopulations

Gnomad AFR exome

AF:

0.000632

Gnomad AMR exome

AF:

0.000362

Gnomad ASJ exome

AF:

0.00282

Gnomad EAS exome

AF:

0.00212

Gnomad FIN exome

AF:

0.0000599

Gnomad NFE exome

AF:

0.000705

Gnomad OTH exome

AF:

0.00205

GnomAD4 exome

AF:

0.00112

AC:

1587

AN:

1417644

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

907

AN XY:

700982

show subpopulations

African (AFR)

AF:

0.000246

AC:

AN:

32586

American (AMR)

AF:

0.000366

AC:

AN:

38274

Ashkenazi Jewish (ASJ)

AF:

0.00335

AC:

AN:

25350

East Asian (EAS)

AF:

0.00324

AC:

122

AN:

37608

South Asian (SAS)

AF:

0.00682

AC:

550

AN:

80644

European-Finnish (FIN)

AF:

0.0000796

AC:

AN:

50250

Middle Eastern (MID)

AF:

0.00403

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.000593

AC:

646

AN:

1088506

Other (OTH)

AF:

0.00230

AC:

135

AN:

58722

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

111

222

333

444

555

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00123

AC:

187

AN:

152366

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

101

AN XY:

74522

show subpopulations

African (AFR)

AF:

0.000433

AC:

AN:

41590

American (AMR)

AF:

0.00118

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3470

East Asian (EAS)

AF:

0.00270

AC:

AN:

5188

South Asian (SAS)

AF:

0.0101

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000941

AC:

AN:

68032

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00123

Hom.:

Bravo

AF:

0.000948

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00137

AC:

ESP6500EA

AF:

0.000584

AC:

ExAC

AF:

0.00141

AC:

168

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

May 26, 2017

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Aug 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

NCF4-related disorder

Benign:1

May 26, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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

0.087

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.65

CADD

Benign

9.2

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.024

T;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.48

T;T;T

MetaRNN

Benign

0.0037

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.20

.;N;N

PhyloP100

0.069

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.50

N;N;N

REVEL

Benign

0.017

Sift

Benign

0.21

T;T;T

Sift4G

Benign

0.24

T;T;T

Polyphen

0.12

.;B;.

Vest4

0.12, 0.10

MVP

0.53

MPC

0.18

ClinPred

0.0011

GERP RS

-1.7

Varity_R

0.016

gMVP

0.28

Mutation Taster

=99/1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over