rs12158689

Positions:

• chr22-36870076-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000631.5(NCF4):​c.343-339G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0245 in 377,912 control chromosomes in the GnomAD database, including 725 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.049 (617 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (108 hom.)
• Consequence: NCF4 NM_000631.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0170

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 22-36870076-G-A is Benign according to our data. Variant chr22-36870076-G-A is described in ClinVar as [Benign]. Clinvar id is 1227207.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-36870076-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCF4	NM_000631.5	c.343-339G>A		intron_variant		ENST00000248899.11	NP_000622.2
NCF4-AS1	NR_147197.1	n.351+17C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCF4	ENST00000248899.11	c.343-339G>A		intron_variant		1	NM_000631.5	ENSP00000248899	P1
NCF4-AS1	ENST00000619915.1	n.349+17C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0492 AC: 7485 AN: 152062 Hom.: 612 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00216

Gnomad OTH AF: 0.0316

GnomAD4 exome AF: 0.00771 AC: 1741 AN: 225732 Hom.: 108 Cov.: 0 AF XY: 0.00659 AC XY: 809 AN XY: 122846

Gnomad4 AFR exome AF: 0.171

Gnomad4 AMR exome AF: 0.0103

Gnomad4 ASJ exome AF: 0.000177

Gnomad4 EAS exome AF: 0.000100

Gnomad4 SAS exome AF: 0.00157

Gnomad4 FIN exome AF: 0.00262

Gnomad4 NFE exome AF: 0.00260

Gnomad4 OTH exome AF: 0.0104

GnomAD4 genome AF: 0.0493 AC: 7503 AN: 152180 Hom.: 617 Cov.: 32 AF XY: 0.0479 AC XY: 3561 AN XY: 74408

Gnomad4 AFR AF: 0.169

Gnomad4 AMR AF: 0.0148

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.00216

Gnomad4 OTH AF: 0.0313

Alfa AF: 0.0301 Hom.: 63

Bravo AF: 0.0556

Asia WGS AF: 0.0140 AC: 48 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 29, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.6
DANN	Benign	0.52

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: rs12158689; hg19: chr22-37266118;