22-36875760-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000631.5(NCF4):c.735C>T(p.Tyr245Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0825 in 1,613,996 control chromosomes in the GnomAD database, including 6,913 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1407 hom., cov: 32)

Exomes 𝑓: 0.079 ( 5506 hom. )

Consequence

NCF4
NM_000631.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -2.20

Publications

14 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 22-36875760-C-T is Benign according to our data. Variant chr22-36875760-C-T is described in ClinVar as Benign. ClinVar VariationId is 260307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.2 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000631.5. 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
	NCF4	NM_000631.5	MANE Select	c.735C>T	p.Tyr245Tyr	synonymous	Exon 8 of 10	NP_000622.2
	NCF4	NM_013416.4		c.735C>T	p.Tyr245Tyr	synonymous	Exon 8 of 9	NP_038202.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NCF4	ENST00000248899.11	TSL:1 MANE Select	c.735C>T	p.Tyr245Tyr	synonymous	Exon 8 of 10	ENSP00000248899.6
NCF4	ENST00000397147.7	TSL:1	c.735C>T	p.Tyr245Tyr	synonymous	Exon 8 of 9	ENSP00000380334.4
NCF4	ENST00000650698.1		c.426C>T	p.Tyr142Tyr	synonymous	Exon 8 of 10	ENSP00000498381.1

Frequencies

GnomAD3 genomes

AF:

0.118

AC:

17946

AN:

152064

Hom.:

1405

Cov.:

show subpopulations

Gnomad AFR

AF:

0.217

Gnomad AMI

AF:

0.0429

Gnomad AMR

AF:

0.151

Gnomad ASJ

AF:

0.0922

Gnomad EAS

AF:

0.0538

Gnomad SAS

AF:

0.106

Gnomad FIN

AF:

0.0573

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0683

Gnomad OTH

AF:

0.114

GnomAD2 exomes

AF:

0.0957

AC:

24056

AN:

251378

AF XY:

0.0921

show subpopulations

Gnomad AFR exome

AF:

0.222

Gnomad AMR exome

AF:

0.175

Gnomad ASJ exome

AF:

0.0875

Gnomad EAS exome

AF:

0.0530

Gnomad FIN exome

AF:

0.0585

Gnomad NFE exome

AF:

0.0662

Gnomad OTH exome

AF:

0.0807

GnomAD4 exome

AF:

0.0787

AC:

115100

AN:

1461814

Hom.:

5506

Cov.:

AF XY:

0.0790

AC XY:

57464

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.227

AC:

7611

AN:

33480

American (AMR)

AF:

0.171

AC:

7640

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0852

AC:

2228

AN:

26136

East Asian (EAS)

AF:

0.0455

AC:

1805

AN:

39698

South Asian (SAS)

AF:

0.108

AC:

9316

AN:

86258

European-Finnish (FIN)

AF:

0.0582

AC:

3107

AN:

53350

Middle Eastern (MID)

AF:

0.0922

AC:

532

AN:

5768

European-Non Finnish (NFE)

AF:

0.0696

AC:

77440

AN:

1112004

Other (OTH)

AF:

0.0898

AC:

5421

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

7321

14642

21962

29283

36604

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3144

6288

9432

12576

15720

<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:

0.118

AC:

17984

AN:

152182

Hom.:

1407

Cov.:

AF XY:

0.118

AC XY:

8787

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.217

AC:

8999

AN:

41478

American (AMR)

AF:

0.151

AC:

2314

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0922

AC:

320

AN:

3470

East Asian (EAS)

AF:

0.0533

AC:

276

AN:

5174

South Asian (SAS)

AF:

0.107

AC:

516

AN:

4832

European-Finnish (FIN)

AF:

0.0573

AC:

608

AN:

10608

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0683

AC:

4647

AN:

68010

Other (OTH)

AF:

0.114

AC:

240

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

786

1573

2359

3146

3932

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

190

380

570

760

950

<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:

0.0827

Hom.:

2868

Bravo

AF:

0.130

Asia WGS

AF:

0.0840

AC:

294

AN:

3478

EpiCase

AF:

0.0707

EpiControl

AF:

0.0702

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.15

(source)

DANN

Benign

0.59

PhyloP100

-2.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over