22-36862461-T-C

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCF4	NM_000631.5	c.32+1258T>C		intron_variant		ENST00000248899.11
NCF4-AS1	NR_147197.1	n.351+7632A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCF4	ENST00000248899.11	c.32+1258T>C		intron_variant		1	NM_000631.5	P1
NCF4-AS1	ENST00000619915.1	n.349+7632A>G		intron_variant, non_coding_transcript_variant		4

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

Gnomad4 AFR AF: 0.589

Gnomad4 AMR AF: 0.311

Gnomad4 ASJ AF: 0.419

Gnomad4 EAS AF: 0.136

Gnomad4 SAS AF: 0.280

Gnomad4 FIN AF: 0.193

Gnomad4 NFE AF: 0.320

Gnomad4 OTH AF: 0.391

Alfa AF: 0.325 Hom.: 18184

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	1.9
Dann	Benign	0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs4821544; hg19: chr22-37258503; COSMIC: COSV50622677;