22-36873514-C-T

Variant names:

• chr22-36873514-C-T
• rs3788524
• NM_000631.5:c.627+1089C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000631.5(NCF4):​c.627+1089C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.861 in 151,928 control chromosomes in the GnomAD database, including 56,635 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.86 (56635 hom., cov: 30)
• Consequence: NCF4 NM_000631.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.250
• Publications: 6 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.938 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.627+1089C>T		intron	N/A	NP_000622.2
	NCF4	NM_013416.4		c.627+1089C>T		intron	N/A	NP_038202.2	Q15080-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCF4	ENST00000248899.11	TSL:1 MANE Select	c.627+1089C>T		intron	N/A	ENSP00000248899.6	Q15080-1
	NCF4	ENST00000397147.7	TSL:1	c.627+1089C>T		intron	N/A	ENSP00000380334.4	Q15080-3
	NCF4	ENST00000650698.1		c.318+1089C>T		intron	N/A	ENSP00000498381.1	A0A494BZS1

Frequencies

GnomAD3 genomes AF: 0.861 AC: 130700 AN: 151812 Hom.: 56570 Cov.: 30

Gnomad AFR AF: 0.946

Gnomad AMI AF: 0.765

Gnomad AMR AF: 0.867

Gnomad ASJ AF: 0.862

Gnomad EAS AF: 0.674

Gnomad SAS AF: 0.797

Gnomad FIN AF: 0.835

Gnomad MID AF: 0.823

Gnomad NFE AF: 0.832

Gnomad OTH AF: 0.859

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

GnomAD4 genome AF: 0.861 AC: 130821 AN: 151928 Hom.: 56635 Cov.: 30 AF XY: 0.859 AC XY: 63787 AN XY: 74234

African (AFR) AF: 0.946 AC: 39166 AN: 41406

American (AMR) AF: 0.867 AC: 13257 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.862 AC: 2991 AN: 3468

East Asian (EAS) AF: 0.673 AC: 3464 AN: 5146

South Asian (SAS) AF: 0.797 AC: 3829 AN: 4802

European-Finnish (FIN) AF: 0.835 AC: 8812 AN: 10556

Middle Eastern (MID) AF: 0.830 AC: 244 AN: 294

European-Non Finnish (NFE) AF: 0.832 AC: 56553 AN: 67944

Other (OTH) AF: 0.858 AC: 1810 AN: 2110

Alfa AF: 0.858 Hom.: 6960

Bravo AF: 0.866

Asia WGS AF: 0.797 AC: 2772 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.95
DANN	Benign	0.73
PhyloP100		-0.25
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3788524; hg19: chr22-37269556;