rs10854695

chr22-36864081-G-Achr22-36864081-G-Cchr22-36864081-G-T

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.69G>A(p.Ser23=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,613,954 control chromosomes in the GnomAD database, including 2,314 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S23S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.069 (938 hom., cov: 31)
  • Exomes 𝑓: 0.013 (1376 hom.)
• Consequence: NCF4 NM_000631.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.406

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 22-36864081-G-A is Benign according to our data. Variant chr22-36864081-G-A is described in ClinVar as [Benign]. Clinvar id is 260306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36864081-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.406 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCF4	NM_000631.5	c.69G>A	p.Ser23=	synonymous_variant	2/10	ENST00000248899.11
NCF4-AS1	NR_147197.1	n.351+6012C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCF4	ENST00000248899.11	c.69G>A	p.Ser23=	synonymous_variant	2/10	1	NM_000631.5	P1
NCF4-AS1	ENST00000619915.1	n.349+6012C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0687 AC: 10440 AN: 151976 Hom.: 935 Cov.: 31

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0933

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.0622

Gnomad SAS AF: 0.0179

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00149

Gnomad OTH AF: 0.0516

GnomAD3 exomes AF: 0.0412 AC: 10371 AN: 251492 Hom.: 787 AF XY: 0.0325 AC XY: 4414 AN XY: 135922

Gnomad AFR exome AF: 0.210

Gnomad AMR exome AF: 0.144

Gnomad ASJ exome AF: 0.00456

Gnomad EAS exome AF: 0.0651

Gnomad SAS exome AF: 0.0137

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00167

Gnomad OTH exome AF: 0.0208

GnomAD4 exome AF: 0.0134 AC: 19572 AN: 1461860 Hom.: 1376 Cov.: 32 AF XY: 0.0121 AC XY: 8788 AN XY: 727238

Gnomad4 AFR exome AF: 0.211

Gnomad4 AMR exome AF: 0.138

Gnomad4 ASJ exome AF: 0.00352

Gnomad4 EAS exome AF: 0.0663

Gnomad4 SAS exome AF: 0.0123

Gnomad4 FIN exome AF: 0.000168

Gnomad4 NFE exome AF: 0.000984

Gnomad4 OTH exome AF: 0.0227

GnomAD4 genome AF: 0.0688 AC: 10465 AN: 152094 Hom.: 938 Cov.: 31 AF XY: 0.0681 AC XY: 5063 AN XY: 74350

Gnomad4 AFR AF: 0.202

Gnomad4 AMR AF: 0.0936

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.0615

Gnomad4 SAS AF: 0.0179

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00149

Gnomad4 OTH AF: 0.0520

Alfa AF: 0.0278 Hom.: 188

Bravo AF: 0.0837

Asia WGS AF: 0.0550 AC: 192 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00284

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

NCF4-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 06, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 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	-0.56
Cadd	Benign	1.5
Dann	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10854695; hg19: chr22-37260123;