rs2072711

Positions:

• chr22-36872513-A-G
• chr22-36872513-A-T

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.627+88A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.835 in 1,152,614 control chromosomes in the GnomAD database, including 402,369 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (56218 hom., cov: 27)
  • Exomes 𝑓: 0.83 (346151 hom.)
• Consequence: NCF4 NM_000631.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.829

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=-0.92).
• BP6: Variant 22-36872513-A-G is Benign according to our data. Variant chr22-36872513-A-G is described in ClinVar as [Benign]. Clinvar id is 1289546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.937 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCF4	NM_000631.5	c.627+88A>G		intron_variant		ENST00000248899.11
NCF4	NM_013416.4	c.627+88A>G		intron_variant
NCF4	XM_047441384.1	c.801+88A>G		intron_variant
NCF4	XM_047441385.1	c.771+88A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCF4	ENST00000248899.11	c.627+88A>G		intron_variant		1	NM_000631.5	P1

Frequencies

GnomAD3 genomes AF: 0.861 AC: 129932 AN: 150942 Hom.: 56151 Cov.: 27

Gnomad AFR AF: 0.945

Gnomad AMI AF: 0.765

Gnomad AMR AF: 0.867

Gnomad ASJ AF: 0.863

Gnomad EAS AF: 0.677

Gnomad SAS AF: 0.798

Gnomad FIN AF: 0.834

Gnomad MID AF: 0.823

Gnomad NFE AF: 0.832

Gnomad OTH AF: 0.860

GnomAD4 exome AF: 0.831 AC: 831906 AN: 1001554 Hom.: 346151 AF XY: 0.830 AC XY: 426989 AN XY: 514530

Gnomad4 AFR exome AF: 0.949

Gnomad4 AMR exome AF: 0.862

Gnomad4 ASJ exome AF: 0.857

Gnomad4 EAS exome AF: 0.711

Gnomad4 SAS exome AF: 0.818

Gnomad4 FIN exome AF: 0.845

Gnomad4 NFE exome AF: 0.830

Gnomad4 OTH exome AF: 0.842

GnomAD4 genome AF: 0.861 AC: 130057 AN: 151060 Hom.: 56218 Cov.: 27 AF XY: 0.860 AC XY: 63414 AN XY: 73766

Gnomad4 AFR AF: 0.945

Gnomad4 AMR AF: 0.867

Gnomad4 ASJ AF: 0.863

Gnomad4 EAS AF: 0.677

Gnomad4 SAS AF: 0.798

Gnomad4 FIN AF: 0.834

Gnomad4 NFE AF: 0.832

Gnomad4 OTH AF: 0.860

Alfa AF: 0.834 Hom.: 107068

Bravo AF: 0.866

Asia WGS AF: 0.798 AC: 2772 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

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 63% of patients studied by a panel of primary immunodeficiencies. Number of patients: 60. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.53
DANN	Benign	0.57

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: rs2072711; hg19: chr22-37268555;