NM_000631.5:c.528+16A>G

Variant names:

• chr22-36871725-A-G
• rs2072708
• NM_000631.5:c.528+16A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000631.5(NCF4):​c.528+16A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.714 in 1,554,170 control chromosomes in the GnomAD database, including 400,398 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (33492 hom., cov: 34)
  • Exomes 𝑓: 0.72 (366906 hom.)
• Consequence: NCF4 NM_000631.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.59
• Publications: 15 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 Gene-Disease associations (from GenCC):

• granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• chronic granulomatous disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 22-36871725-A-G is Benign according to our data. Variant chr22-36871725-A-G is described in ClinVar as Benign. ClinVar VariationId is 198201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000631.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCF4	NM_000631.5	MANE Select	c.528+16A>G		intron	N/A	NP_000622.2
	NCF4	NM_013416.4		c.528+16A>G		intron	N/A	NP_038202.2	Q15080-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCF4	ENST00000248899.11	TSL:1 MANE Select	c.528+16A>G		intron	N/A	ENSP00000248899.6	Q15080-1
	NCF4	ENST00000397147.7	TSL:1	c.528+16A>G		intron	N/A	ENSP00000380334.4	Q15080-3
	NCF4	ENST00000650698.1		c.219+16A>G		intron	N/A	ENSP00000498381.1	A0A494BZS1

Frequencies

GnomAD3 genomes AF: 0.650 AC: 98810 AN: 152054 Hom.: 33476 Cov.: 34

Gnomad AFR AF: 0.437

Gnomad AMI AF: 0.620

Gnomad AMR AF: 0.751

Gnomad ASJ AF: 0.784

Gnomad EAS AF: 0.677

Gnomad SAS AF: 0.738

Gnomad FIN AF: 0.717

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.731

Gnomad OTH AF: 0.664

GnomAD2 exomes AF: 0.718 AC: 115428 AN: 160718 AF XY: 0.723

Gnomad AFR exome AF: 0.422

Gnomad AMR exome AF: 0.786

Gnomad ASJ exome AF: 0.783

Gnomad EAS exome AF: 0.657

Gnomad FIN exome AF: 0.726

Gnomad NFE exome AF: 0.724

Gnomad OTH exome AF: 0.710

GnomAD4 exome AF: 0.721 AC: 1011328 AN: 1401998 Hom.: 366906 Cov.: 53 AF XY: 0.723 AC XY: 500226 AN XY: 691898

African (AFR) AF: 0.417 AC: 13292 AN: 31876

American (AMR) AF: 0.781 AC: 28197 AN: 36094

Ashkenazi Jewish (ASJ) AF: 0.778 AC: 19613 AN: 25196

East Asian (EAS) AF: 0.709 AC: 25590 AN: 36104

South Asian (SAS) AF: 0.747 AC: 59399 AN: 79476

European-Finnish (FIN) AF: 0.734 AC: 36118 AN: 49184

Middle Eastern (MID) AF: 0.610 AC: 3459 AN: 5668

European-Non Finnish (NFE) AF: 0.726 AC: 784211 AN: 1080286

Other (OTH) AF: 0.713 AC: 41449 AN: 58114

GnomAD4 genome AF: 0.650 AC: 98855 AN: 152172 Hom.: 33492 Cov.: 34 AF XY: 0.653 AC XY: 48554 AN XY: 74406

African (AFR) AF: 0.437 AC: 18141 AN: 41496

American (AMR) AF: 0.751 AC: 11493 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.784 AC: 2721 AN: 3472

East Asian (EAS) AF: 0.676 AC: 3493 AN: 5164

South Asian (SAS) AF: 0.737 AC: 3555 AN: 4824

European-Finnish (FIN) AF: 0.717 AC: 7598 AN: 10596

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.731 AC: 49710 AN: 68004

Other (OTH) AF: 0.666 AC: 1407 AN: 2114

Alfa AF: 0.698 Hom.: 6902

Bravo AF: 0.639

Asia WGS AF: 0.728 AC: 2531 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.39
DANN	Benign	0.071
PhyloP100		-1.6
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: rs2072708; hg19: chr22-37267767; COSMIC: COSV50620686; COSMIC: COSV50620686;