22-36862461-T-C

Variant names:

• chr22-36862461-T-C
• rs4821544
• NM_000631.5:c.32+1258T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.823
• Publications: 74 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 -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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	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
	NCF4-AS1	NR_147197.1		n.351+7632A>G		intron	N/A

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes AF: 0.379 AC: 57640 AN: 151970 Hom.: 12508 Cov.: 33

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.: 33 AF XY: 0.371 AC XY: 27611 AN XY: 74352

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

Alfa AF: 0.335 Hom.: 29313

Bravo AF: 0.396

Asia WGS AF: 0.270 AC: 938 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.9
DANN	Benign	0.65
PhyloP100		-0.82
PromoterAI		-0.032	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: rs4821544; hg19: chr22-37258503; COSMIC: COSV50622677;