rs2072706

Variant names:

• chr22-36870937-A-G
• rs2072706
• NM_000631.5:c.470+395A>G

Variant summary

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

The NM_000631.5(NCF4):​c.470+395A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.654 in 152,066 control chromosomes in the GnomAD database, including 32,703 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 0.65 (32703 hom., cov: 31)
• Consequence: NCF4 NM_000631.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.65
• Publications: 5 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.67 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.470+395A>G		intron	N/A	NP_000622.2
	NCF4	NM_013416.4		c.470+395A>G		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.470+395A>G		intron	N/A	ENSP00000248899.6	Q15080-1
	NCF4	ENST00000397147.7	TSL:1	c.470+395A>G		intron	N/A	ENSP00000380334.4	Q15080-3
	NCF4	ENST00000650698.1		c.161+395A>G		intron	N/A	ENSP00000498381.1	A0A494BZS1

Frequencies

GnomAD3 genomes AF: 0.654 AC: 99425 AN: 151948 Hom.: 32675 Cov.: 31

Gnomad AFR AF: 0.607

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.650

Gnomad ASJ AF: 0.709

Gnomad EAS AF: 0.629

Gnomad SAS AF: 0.630

Gnomad FIN AF: 0.729

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.675

Gnomad OTH AF: 0.651

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

GnomAD4 genome AF: 0.654 AC: 99497 AN: 152066 Hom.: 32703 Cov.: 31 AF XY: 0.657 AC XY: 48819 AN XY: 74344

African (AFR) AF: 0.607 AC: 25160 AN: 41464

American (AMR) AF: 0.651 AC: 9942 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.709 AC: 2457 AN: 3466

East Asian (EAS) AF: 0.629 AC: 3250 AN: 5166

South Asian (SAS) AF: 0.628 AC: 3030 AN: 4822

European-Finnish (FIN) AF: 0.729 AC: 7712 AN: 10584

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.675 AC: 45875 AN: 67978

Other (OTH) AF: 0.652 AC: 1374 AN: 2106

Alfa AF: 0.670 Hom.: 4247

Bravo AF: 0.645

Asia WGS AF: 0.674 AC: 2343 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.027
DANN	Benign	0.54
PhyloP100		-4.6
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: rs2072706; hg19: chr22-37266979;