rs12158689

Variant names:

• chr22-36870076-G-A
• rs12158689
• NM_000631.5:c.343-339G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 1227207.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 rank	MANE	Protein	UniProt
NCF4	NM_000631.5	c.343-339G>A		intron_variant	Intron 4 of 9	ENST00000248899.11	NP_000622.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCF4	ENST00000248899.11	c.343-339G>A		intron_variant	Intron 4 of 9	1	NM_000631.5	ENSP00000248899.6

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

African (AFR) AF: 0.171 AC: 1069 AN: 6244

American (AMR) AF: 0.0103 AC: 121 AN: 11746

Ashkenazi Jewish (ASJ) AF: 0.000177 AC: 1 AN: 5648

East Asian (EAS) AF: 0.000100 AC: 1 AN: 9984

South Asian (SAS) AF: 0.00157 AC: 66 AN: 41938

European-Finnish (FIN) AF: 0.00262 AC: 26 AN: 9932

Middle Eastern (MID) AF: 0.00614 AC: 5 AN: 814

European-Non Finnish (NFE) AF: 0.00260 AC: 333 AN: 128012

Other (OTH) AF: 0.0104 AC: 119 AN: 11414

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

African (AFR) AF: 0.169 AC: 7006 AN: 41474

American (AMR) AF: 0.0148 AC: 226 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4826

European-Finnish (FIN) AF: 0.00424 AC: 45 AN: 10606

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00216 AC: 147 AN: 68022

Other (OTH) AF: 0.0313 AC: 66 AN: 2108

Alfa AF: 0.0361 Hom.: 77

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

Jun 29, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.6
DANN	Benign	0.52
PhyloP100		0.017
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12158689; hg19: chr22-37266118;