rs2072708

Positions:

• chr22-36871725-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000631.5(NCF4):​c.528+16A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.714 in 1,554,170 control chromosomes in the GnomAD database, including 400,398 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (33492 hom., cov: 34)
  • Exomes 𝑓: 0.72 (366906 hom.)
• Consequence: NCF4 NM_000631.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.59

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 22-36871725-A-G is Benign according to our data. Variant chr22-36871725-A-G is described in ClinVar as [Benign]. Clinvar id is 198201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36871725-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCF4	NM_000631.5	c.528+16A>G		intron_variant		ENST00000248899.11
NCF4	NM_013416.4	c.528+16A>G		intron_variant
NCF4	XM_047441384.1	c.702+16A>G		intron_variant
NCF4	XM_047441385.1	c.672+16A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCF4	ENST00000248899.11	c.528+16A>G		intron_variant		1	NM_000631.5	P1

Frequencies

GnomAD3 genomes AF: 0.650 AC: 98810 AN: 152054 Hom.: 33476 Cov.: 34

Gnomad AFR AF: 0.437

Gnomad AMI AF: 0.620

Gnomad AMR AF: 0.751

Gnomad ASJ AF: 0.784

Gnomad EAS AF: 0.677

Gnomad SAS AF: 0.738

Gnomad FIN AF: 0.717

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.731

Gnomad OTH AF: 0.664

GnomAD3 exomes AF: 0.718 AC: 115428 AN: 160718 Hom.: 41860 AF XY: 0.723 AC XY: 61355 AN XY: 84850

Gnomad AFR exome AF: 0.422

Gnomad AMR exome AF: 0.786

Gnomad ASJ exome AF: 0.783

Gnomad EAS exome AF: 0.657

Gnomad SAS exome AF: 0.752

Gnomad FIN exome AF: 0.726

Gnomad NFE exome AF: 0.724

Gnomad OTH exome AF: 0.710

GnomAD4 exome AF: 0.721 AC: 1011328 AN: 1401998 Hom.: 366906 Cov.: 53 AF XY: 0.723 AC XY: 500226 AN XY: 691898

Gnomad4 AFR exome AF: 0.417

Gnomad4 AMR exome AF: 0.781

Gnomad4 ASJ exome AF: 0.778

Gnomad4 EAS exome AF: 0.709

Gnomad4 SAS exome AF: 0.747

Gnomad4 FIN exome AF: 0.734

Gnomad4 NFE exome AF: 0.726

Gnomad4 OTH exome AF: 0.713

GnomAD4 genome AF: 0.650 AC: 98855 AN: 152172 Hom.: 33492 Cov.: 34 AF XY: 0.653 AC XY: 48554 AN XY: 74406

Gnomad4 AFR AF: 0.437

Gnomad4 AMR AF: 0.751

Gnomad4 ASJ AF: 0.784

Gnomad4 EAS AF: 0.676

Gnomad4 SAS AF: 0.737

Gnomad4 FIN AF: 0.717

Gnomad4 NFE AF: 0.731

Gnomad4 OTH AF: 0.666

Alfa AF: 0.698 Hom.: 6902

Bravo AF: 0.639

Asia WGS AF: 0.728 AC: 2531 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 14, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 96% of patients studied by a panel of primary immunodeficiencies. Number of patients: 91. Only high quality variants are reported. -

Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.39
DANN	Benign	0.071

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: rs2072708; hg19: chr22-37267767; COSMIC: COSV50620686; COSMIC: COSV50620686;