rs11552115

Positions:

• chr22-36877700-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000631.5(NCF4):​c.897G>A​(p.Ser299=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0828 in 1,613,982 control chromosomes in the GnomAD database, including 7,021 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1462 hom., cov: 32)
  • Exomes 𝑓: 0.079 (5559 hom.)
• Consequence: NCF4 NM_000631.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.07

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 22-36877700-G-A is Benign according to our data. Variant chr22-36877700-G-A is described in ClinVar as [Benign]. Clinvar id is 260303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36877700-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCF4	NM_000631.5	c.897G>A	p.Ser299=	synonymous_variant	10/10	ENST00000248899.11
NCF4	XM_047441384.1	c.1071G>A	p.Ser357=	synonymous_variant	11/11
NCF4	XM_047441385.1	c.1041G>A	p.Ser347=	synonymous_variant	11/11
NCF4	NM_013416.4	c.*95G>A		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCF4	ENST00000248899.11	c.897G>A	p.Ser299=	synonymous_variant	10/10	1	NM_000631.5	P1

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18189 AN: 152008 Hom.: 1458 Cov.: 32

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.0922

Gnomad EAS AF: 0.0538

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0572

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0682

Gnomad OTH AF: 0.115

GnomAD3 exomes AF: 0.0963 AC: 24197 AN: 251340 Hom.: 1551 AF XY: 0.0926 AC XY: 12584 AN XY: 135858

Gnomad AFR exome AF: 0.229

Gnomad AMR exome AF: 0.175

Gnomad ASJ exome AF: 0.0877

Gnomad EAS exome AF: 0.0531

Gnomad SAS exome AF: 0.106

Gnomad FIN exome AF: 0.0587

Gnomad NFE exome AF: 0.0663

Gnomad OTH exome AF: 0.0808

GnomAD4 exome AF: 0.0790 AC: 115424 AN: 1461856 Hom.: 5559 Cov.: 31 AF XY: 0.0792 AC XY: 57611 AN XY: 727230

Gnomad4 AFR exome AF: 0.233

Gnomad4 AMR exome AF: 0.171

Gnomad4 ASJ exome AF: 0.0853

Gnomad4 EAS exome AF: 0.0457

Gnomad4 SAS exome AF: 0.108

Gnomad4 FIN exome AF: 0.0584

Gnomad4 NFE exome AF: 0.0697

Gnomad4 OTH exome AF: 0.0903

GnomAD4 genome AF: 0.120 AC: 18228 AN: 152126 Hom.: 1462 Cov.: 32 AF XY: 0.120 AC XY: 8902 AN XY: 74394

Gnomad4 AFR AF: 0.223

Gnomad4 AMR AF: 0.151

Gnomad4 ASJ AF: 0.0922

Gnomad4 EAS AF: 0.0533

Gnomad4 SAS AF: 0.107

Gnomad4 FIN AF: 0.0572

Gnomad4 NFE AF: 0.0683

Gnomad4 OTH AF: 0.115

Alfa AF: 0.0918 Hom.: 410

Bravo AF: 0.132

Asia WGS AF: 0.0850 AC: 296 AN: 3478

EpiCase AF: 0.0707

EpiControl AF: 0.0702

ClinVar

Significance: Benign

Submissions summary: Benign:5

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -
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 21% of patients studied by a panel of primary immunodeficiencies. Number of patients: 20. Only high quality variants are reported. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.063
DANN	Benign	0.71

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: rs11552115; hg19: chr22-37273742;