chr22-36862802-G-A

Variant names:

• chr22-36862802-G-A
• rs741998
• NM_000631.5:c.33-1243G>A

Variant summary

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

The NM_000631.5(NCF4):​c.33-1243G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 152,198 control chromosomes in the GnomAD database, including 2,653 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 0.17 (2653 hom., cov: 33)
• Consequence: NCF4 NM_000631.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.184
• Publications: 7 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.293 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCF4	NM_000631.5	MANE Select	c.33-1243G>A		intron	N/A	NP_000622.2
	NCF4	NM_013416.4		c.33-1243G>A		intron	N/A	NP_038202.2
	NCF4-AS1	NR_147197.1		n.351+7291C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCF4	ENST00000248899.11	TSL:1 MANE Select	c.33-1243G>A		intron	N/A	ENSP00000248899.6
	NCF4	ENST00000397147.7	TSL:1	c.33-1243G>A		intron	N/A	ENSP00000380334.4
	NCF4	ENST00000650827.1		c.-278+415G>A		intron	N/A	ENSP00000498212.1

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25848 AN: 152080 Hom.: 2642 Cov.: 33

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.0912

Gnomad ASJ AF: 0.0802

Gnomad EAS AF: 0.0631

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.151

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

GnomAD4 genome AF: 0.170 AC: 25907 AN: 152198 Hom.: 2653 Cov.: 33 AF XY: 0.168 AC XY: 12468 AN XY: 74410

African (AFR) AF: 0.298 AC: 12346 AN: 41496

American (AMR) AF: 0.0911 AC: 1395 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0802 AC: 278 AN: 3468

East Asian (EAS) AF: 0.0631 AC: 327 AN: 5184

South Asian (SAS) AF: 0.115 AC: 555 AN: 4830

European-Finnish (FIN) AF: 0.153 AC: 1628 AN: 10606

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.131 AC: 8882 AN: 67984

Other (OTH) AF: 0.151 AC: 320 AN: 2114

Alfa AF: 0.144 Hom.: 3668

Bravo AF: 0.171

Asia WGS AF: 0.105 AC: 364 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.8
DANN	Benign	0.88
PhyloP100		-0.18
PromoterAI		-0.027	Neutral
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: rs741998; hg19: chr22-37258844;