dbSNP rs4821544: NCF4:c.32+1258T>C (chr22-36862461-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_000631.5(NCF4):c.32+1258T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 152,088 control chromosomes in the GnomAD database, including 12,532 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.38 ( 12532 hom., cov: 33)

Consequence

NCF4
NM_000631.5 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.823

Publications

75 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 links:

NCF4-AS1 (HGNC:40393): (NCF4 antisense RNA 1)

NCF4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 22-36862461-T-C is Benign according to our data. Variant chr22-36862461-T-C is described in ClinVar as Benign. ClinVar VariationId is 1165017.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.583 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NCF4	NM_000631.5	MANE Select	c.32+1258T>C	intron	N/A	NP_000622.2
NCF4	NM_013416.4		c.32+1258T>C	intron	N/A	NP_038202.2	Q15080-3
NCF4-AS1	NR_147197.1		n.351+7632A>G	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NCF4	ENST00000248899.11	TSL:1 MANE Select	c.32+1258T>C	intron	N/A	ENSP00000248899.6	Q15080-1
NCF4	ENST00000397147.7	TSL:1	c.32+1258T>C	intron	N/A	ENSP00000380334.4	Q15080-3
NCF4	ENST00000650827.1		c.-278+74T>C	intron	N/A	ENSP00000498212.1	A0A494BZS1

Frequencies

GnomAD3 genomes

AF:

0.379

AC:

57640

AN:

151970

Hom.:

12508

Cov.:

show subpopulations

Gnomad AFR

AF:

0.589

Gnomad AMI

AF:

0.378

Gnomad AMR

AF:

0.311

Gnomad ASJ

AF:

0.419

Gnomad EAS

AF:

0.136

Gnomad SAS

AF:

0.281

Gnomad FIN

AF:

0.193

Gnomad MID

AF:

0.351

Gnomad NFE

AF:

0.320

Gnomad OTH

AF:

0.389

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.379

AC:

57708

AN:

152088

Hom.:

12532

Cov.:

AF XY:

0.371

AC XY:

27611

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.589

AC:

24420

AN:

41462

American (AMR)

AF:

0.311

AC:

4754

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.419

AC:

1453

AN:

3470

East Asian (EAS)

AF:

0.136

AC:

702

AN:

5166

South Asian (SAS)

AF:

0.280

AC:

1351

AN:

4830

European-Finnish (FIN)

AF:

0.193

AC:

2041

AN:

10590

Middle Eastern (MID)

AF:

0.354

AC:

104

AN:

294

European-Non Finnish (NFE)

AF:

0.320

AC:

21715

AN:

67960

Other (OTH)

AF:

0.391

AC:

824

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1749

3499

5248

6998

8747

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

522

1044

1566

2088

2610

<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:

0.335

Hom.:

29313

Bravo

AF:

0.396

Asia WGS

AF:

0.270

AC:

938

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

-0.87

CADD

Benign

1.9

(source)

DANN

Benign

0.65

PhyloP100

-0.82

PromoterAI

-0.032

Neutral

(source)

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over