rs79312013

Positions:

• chr22-36870411-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000631.5(NCF4):​c.343-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 1,613,768 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (16 hom.)
• Consequence: NCF4 NM_000631.5 splice_region, intron
• Scores: Splicing: ADA: 0.0005640
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.50

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 22-36870411-A-G is Benign according to our data. Variant chr22-36870411-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 471812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36870411-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00329 (501/152204) while in subpopulation NFE AF= 0.0036 (245/68000). AF 95% confidence interval is 0.00323. There are 4 homozygotes in gnomad4. There are 300 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCF4	NM_000631.5	c.343-4A>G		splice_region_variant, intron_variant		ENST00000248899.11	NP_000622.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCF4	ENST00000248899.11	c.343-4A>G		splice_region_variant, intron_variant		1	NM_000631.5	ENSP00000248899.6

Frequencies

GnomAD3 genomes AF: 0.00329 AC: 501 AN: 152086 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00360

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00308 AC: 774 AN: 251056 Hom.: 6 AF XY: 0.00309 AC XY: 419 AN XY: 135728

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00744

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.0169

Gnomad NFE exome AF: 0.00246

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00305 AC: 4464 AN: 1461564 Hom.: 16 Cov.: 32 AF XY: 0.00303 AC XY: 2203 AN XY: 727088

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00731

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000441

Gnomad4 FIN exome AF: 0.0155

Gnomad4 NFE exome AF: 0.00287

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00329 AC: 501 AN: 152204 Hom.: 4 Cov.: 32 AF XY: 0.00403 AC XY: 300 AN XY: 74420

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0189

Gnomad4 NFE AF: 0.00360

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00287 Hom.: 3

Bravo AF: 0.00190

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00256

EpiControl AF: 0.00296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	See Variant Classification Assertion Criteria. -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

NCF4-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 02, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.055
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00056
dbscSNV1_RF	Benign	0.10
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: rs79312013; hg19: chr22-37266453;