22-36871727-G-C

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+18G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00974 in 1,552,934 control chromosomes in the GnomAD database, including 1,266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (659 hom., cov: 35)
  • Exomes 𝑓: 0.0052 (607 hom.)
• Consequence: NCF4 NM_000631.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.53

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=-0.87).
• BP6: Variant 22-36871727-G-C is Benign according to our data. Variant chr22-36871727-G-C is described in ClinVar as [Benign]. Clinvar id is 260304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCF4	NM_000631.5	c.528+18G>C		intron_variant		ENST00000248899.11
NCF4	NM_013416.4	c.528+18G>C		intron_variant
NCF4	XM_047441384.1	c.702+18G>C		intron_variant
NCF4	XM_047441385.1	c.672+18G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCF4	ENST00000248899.11	c.528+18G>C		intron_variant		1	NM_000631.5	P1

Frequencies

GnomAD3 genomes AF: 0.0509 AC: 7750 AN: 152158 Hom.: 657 Cov.: 35

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0155

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.0368

GnomAD3 exomes AF: 0.0126 AC: 2001 AN: 158302 Hom.: 175 AF XY: 0.00910 AC XY: 760 AN XY: 83522

Gnomad AFR exome AF: 0.191

Gnomad AMR exome AF: 0.00862

Gnomad ASJ exome AF: 0.000469

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000349

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000374

Gnomad OTH exome AF: 0.00517

GnomAD4 exome AF: 0.00525 AC: 7348 AN: 1400658 Hom.: 607 Cov.: 35 AF XY: 0.00449 AC XY: 3106 AN XY: 691084

Gnomad4 AFR exome AF: 0.188

Gnomad4 AMR exome AF: 0.0106

Gnomad4 ASJ exome AF: 0.000119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000403

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000212

Gnomad4 OTH exome AF: 0.0120

GnomAD4 genome AF: 0.0511 AC: 7777 AN: 152276 Hom.: 659 Cov.: 35 AF XY: 0.0488 AC XY: 3634 AN XY: 74448

Gnomad4 AFR AF: 0.179

Gnomad4 AMR AF: 0.0154

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.0364

Alfa AF: 0.00375 Hom.: 5

Bravo AF: 0.0581

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.20
Dann	Benign	0.27

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: rs6000455; hg19: chr22-37267769;