chr22-36875840-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000397147.7(NCF4):c.815T>C(p.Leu272Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.831 in 1,614,022 control chromosomes in the GnomAD database, including 558,514 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.86 ( 56740 hom., cov: 31)

Exomes 𝑓: 0.83 ( 501774 hom. )

Consequence

NCF4
ENST00000397147.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 0.298

Publications

39 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=1.1522777E-6).

BP6

Variant 22-36875840-T-C is Benign according to our data. Variant chr22-36875840-T-C is described in ClinVar as Benign. ClinVar VariationId is 260308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.938 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCF4	NM_000631.5 link	c.758+57T>C		intron_variant	Intron 8 of 9	ENST00000248899.11	NP_000622.2	Q15080-1
NCF4	NM_013416.4 link	c.815T>C	p.Leu272Pro	missense_variant	Exon 8 of 9		NP_038202.2	Q15080-3
NCF4	XM_047441384.1 link	c.932+57T>C		intron_variant	Intron 9 of 10		XP_047297340.1
NCF4	XM_047441385.1 link	c.902+57T>C		intron_variant	Intron 9 of 10		XP_047297341.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCF4	ENST00000248899.11 link	c.758+57T>C		intron_variant	Intron 8 of 9	1	NM_000631.5	ENSP00000248899.6		Q15080-1

Frequencies

GnomAD3 genomes

AF:

0.861

AC:

130923

AN:

152054

Hom.:

56674

Cov.:

show subpopulations

Gnomad AFR

AF:

0.946

Gnomad AMI

AF:

0.765

Gnomad AMR

AF:

0.866

Gnomad ASJ

AF:

0.862

Gnomad EAS

AF:

0.673

Gnomad SAS

AF:

0.797

Gnomad FIN

AF:

0.835

Gnomad MID

AF:

0.823

Gnomad NFE

AF:

0.832

Gnomad OTH

AF:

0.858

GnomAD2 exomes

AF:

0.831

AC:

208985

AN:

251444

AF XY:

0.828

show subpopulations

Gnomad AFR exome

AF:

0.948

Gnomad AMR exome

AF:

0.859

Gnomad ASJ exome

AF:

0.859

Gnomad EAS exome

AF:

0.662

Gnomad FIN exome

AF:

0.837

Gnomad NFE exome

AF:

0.833

Gnomad OTH exome

AF:

0.833

GnomAD4 exome

AF:

0.828

AC:

1210107

AN:

1461850

Hom.:

501774

Cov.:

AF XY:

0.828

AC XY:

601888

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.952

AC:

31884

AN:

33480

American (AMR)

AF:

0.861

AC:

38497

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.855

AC:

22335

AN:

26134

East Asian (EAS)

AF:

0.692

AC:

27472

AN:

39690

South Asian (SAS)

AF:

0.816

AC:

70428

AN:

86258

European-Finnish (FIN)

AF:

0.844

AC:

45098

AN:

53412

Middle Eastern (MID)

AF:

0.828

AC:

4777

AN:

5768

European-Non Finnish (NFE)

AF:

0.826

AC:

918940

AN:

1111988

Other (OTH)

AF:

0.839

AC:

50676

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

14793

29585

44378

59170

73963

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20996

41992

62988

83984

104980

<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:

0.861

AC:

131046

AN:

152172

Hom.:

56740

Cov.:

AF XY:

0.859

AC XY:

63932

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.946

AC:

39293

AN:

41534

American (AMR)

AF:

0.867

AC:

13258

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.862

AC:

2993

AN:

3472

East Asian (EAS)

AF:

0.672

AC:

3477

AN:

5172

South Asian (SAS)

AF:

0.798

AC:

3844

AN:

4820

European-Finnish (FIN)

AF:

0.835

AC:

8835

AN:

10576

Middle Eastern (MID)

AF:

0.830

AC:

244

AN:

294

European-Non Finnish (NFE)

AF:

0.832

AC:

56592

AN:

67982

Other (OTH)

AF:

0.857

AC:

1812

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

917

1834

2752

3669

4586

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

892

1784

2676

3568

4460

<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:

0.848

Hom.:

48960

Bravo

AF:

0.866

TwinsUK

AF:

0.836

AC:

3100

ALSPAC

AF:

0.835

AC:

3217

ESP6500AA

AF:

0.938

AC:

4132

ESP6500EA

AF:

0.835

AC:

7184

ExAC

AF:

0.834

AC:

101201

Asia WGS

AF:

0.799

AC:

2779

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 96% of patients studied by a panel of primary immunodeficiencies. Number of patients: 91. Only high quality variants are reported. -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

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

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

0.047

(source)

DANN

Benign

0.96

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.000090

LIST_S2

Benign

0.15

MetaRNN

Benign

0.0000012

MetaSVM

Benign

-0.96

PhyloP100

0.30

PROVEAN

Benign

-0.42

REVEL

Benign

0.12

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0060

Vest4

0.036

MPC

0.73

ClinPred

0.011

GERP RS

-0.74

gMVP

0.53

Mutation Taster

=98/2

polymorphism (auto)

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over