22-36869037-G-C

Variant names:

• chr22-36869037-G-C
• rs2284027
• NM_000631.5:c.343-1378G>C

Variant summary

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

The NM_000631.5(NCF4):​c.343-1378G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.697 in 152,074 control chromosomes in the GnomAD database, including 38,623 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 0.70 (38623 hom., cov: 32)
• Consequence: NCF4 NM_000631.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.591
• Publications: 9 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-AS1 (HGNC:40393): (NCF4 antisense RNA 1)

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 = 0.802 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.343-1378G>C		intron	N/A	NP_000622.2
	NCF4	NM_013416.4		c.343-1378G>C		intron	N/A	NP_038202.2	Q15080-3
	NCF4-AS1	NR_147197.1		n.351+1056C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCF4	ENST00000248899.11	TSL:1 MANE Select	c.343-1378G>C		intron	N/A	ENSP00000248899.6	Q15080-1
	NCF4	ENST00000397147.7	TSL:1	c.343-1378G>C		intron	N/A	ENSP00000380334.4	Q15080-3
	NCF4	ENST00000650698.1		c.34-1378G>C		intron	N/A	ENSP00000498381.1	A0A494BZS1

Frequencies

GnomAD3 genomes AF: 0.697 AC: 105881 AN: 151956 Hom.: 38612 Cov.: 32

Gnomad AFR AF: 0.465

Gnomad AMI AF: 0.729

Gnomad AMR AF: 0.725

Gnomad ASJ AF: 0.841

Gnomad EAS AF: 0.615

Gnomad SAS AF: 0.733

Gnomad FIN AF: 0.814

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.808

Gnomad OTH AF: 0.721

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

GnomAD4 genome AF: 0.697 AC: 105924 AN: 152074 Hom.: 38623 Cov.: 32 AF XY: 0.697 AC XY: 51778 AN XY: 74332

African (AFR) AF: 0.465 AC: 19260 AN: 41438

American (AMR) AF: 0.725 AC: 11083 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.841 AC: 2920 AN: 3472

East Asian (EAS) AF: 0.616 AC: 3173 AN: 5154

South Asian (SAS) AF: 0.732 AC: 3533 AN: 4826

European-Finnish (FIN) AF: 0.814 AC: 8599 AN: 10570

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.808 AC: 54960 AN: 68020

Other (OTH) AF: 0.721 AC: 1521 AN: 2110

Alfa AF: 0.698 Hom.: 2404

Bravo AF: 0.676

Asia WGS AF: 0.712 AC: 2477 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	0.45
DANN	Benign	0.39
PhyloP100		-0.59
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: rs2284027; hg19: chr22-37265079;