rs56071149

Variant names:

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.628-14C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0173 in 1,609,904 control chromosomes in the GnomAD database, including 304 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 13 hom., cov: 32)

Exomes 𝑓: 0.018 ( 291 hom. )

Consequence

NCF4
NM_000631.5 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.657

Publications

2 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 (BayesDel_noAF=-0.8).

BP6

Variant 22-36875639-C-A is Benign according to our data. Variant chr22-36875639-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260305.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 = 0.012 (1829/152256) while in subpopulation SAS AF = 0.0278 (134/4812). AF 95% confidence interval is 0.024. There are 13 homozygotes in GnomAd4. There are 862 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

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.628-14C>A		intron	N/A	NP_000622.2
	NCF4	NM_013416.4		c.628-14C>A		intron	N/A	NP_038202.2	Q15080-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NCF4	ENST00000248899.11	TSL:1 MANE Select	c.628-14C>A	intron	N/A	ENSP00000248899.6	Q15080-1
NCF4	ENST00000397147.7	TSL:1	c.628-14C>A	intron	N/A	ENSP00000380334.4	Q15080-3
NCF4	ENST00000650698.1		c.319-14C>A	intron	N/A	ENSP00000498381.1	A0A494BZS1

Frequencies

GnomAD3 genomes

AF:

0.0120

AC:

1832

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00282

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00890

Gnomad ASJ

AF:

0.0366

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0282

Gnomad FIN

AF:

0.00565

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0179

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.0152

AC:

3762

AN:

247390

AF XY:

0.0164

show subpopulations

Gnomad AFR exome

AF:

0.00231

Gnomad AMR exome

AF:

0.00654

Gnomad ASJ exome

AF:

0.0411

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00478

Gnomad NFE exome

AF:

0.0188

Gnomad OTH exome

AF:

0.0153

GnomAD4 exome

AF:

0.0178

AC:

26013

AN:

1457648

Hom.:

291

Cov.:

AF XY:

0.0184

AC XY:

13313

AN XY:

725292

show subpopulations

African (AFR)

AF:

0.00281

AC:

AN:

33468

American (AMR)

AF:

0.00740

AC:

331

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0399

AC:

1042

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39690

South Asian (SAS)

AF:

0.0288

AC:

2485

AN:

86252

European-Finnish (FIN)

AF:

0.00563

AC:

280

AN:

49720

Middle Eastern (MID)

AF:

0.0392

AC:

226

AN:

5762

European-Non Finnish (NFE)

AF:

0.0183

AC:

20309

AN:

1111558

Other (OTH)

AF:

0.0206

AC:

1245

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1364

2728

4093

5457

6821

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

752

1504

2256

3008

3760

<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:

0.0120

AC:

1829

AN:

152256

Hom.:

Cov.:

AF XY:

0.0116

AC XY:

862

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00282

AC:

117

AN:

41562

American (AMR)

AF:

0.00889

AC:

136

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0366

AC:

127

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.0278

AC:

134

AN:

4812

European-Finnish (FIN)

AF:

0.00565

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0179

AC:

1218

AN:

67998

Other (OTH)

AF:

0.0119

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

184

277

369

461

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0158

Hom.:

Bravo

AF:

0.0114

Asia WGS

AF:

0.0160

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

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

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

2.7

(source)

DANN

Benign

0.71

PhyloP100

-0.66

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over