22-36873465-T-C

Variant names:

• chr22-36873465-T-C
• rs3788523
• NM_000631.5:c.627+1040T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000631.5(NCF4):​c.627+1040T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.568 in 151,322 control chromosomes in the GnomAD database, including 26,158 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.57 (26158 hom., cov: 29)
• Consequence: NCF4 NM_000631.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.64
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.661 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCF4	NM_000631.5	c.627+1040T>C		intron_variant	Intron 7 of 9	ENST00000248899.11	NP_000622.2
NCF4	NM_013416.4	c.627+1040T>C		intron_variant	Intron 7 of 8		NP_038202.2
NCF4	XM_047441384.1	c.801+1040T>C		intron_variant	Intron 8 of 10		XP_047297340.1
NCF4	XM_047441385.1	c.771+1040T>C		intron_variant	Intron 8 of 10		XP_047297341.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCF4	ENST00000248899.11	c.627+1040T>C		intron_variant	Intron 7 of 9	1	NM_000631.5	ENSP00000248899.6

Frequencies

GnomAD3 genomes AF: 0.568 AC: 85887 AN: 151208 Hom.: 26149 Cov.: 29

Gnomad AFR AF: 0.325

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.609

Gnomad ASJ AF: 0.691

Gnomad EAS AF: 0.617

Gnomad SAS AF: 0.621

Gnomad FIN AF: 0.725

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.666

Gnomad OTH AF: 0.578

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.568 AC: 85911 AN: 151322 Hom.: 26158 Cov.: 29 AF XY: 0.572 AC XY: 42319 AN XY: 73942

African (AFR) AF: 0.325 AC: 13304 AN: 40910

American (AMR) AF: 0.610 AC: 9304 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.691 AC: 2398 AN: 3468

East Asian (EAS) AF: 0.617 AC: 3169 AN: 5136

South Asian (SAS) AF: 0.619 AC: 2968 AN: 4796

European-Finnish (FIN) AF: 0.725 AC: 7653 AN: 10560

Middle Eastern (MID) AF: 0.514 AC: 151 AN: 294

European-Non Finnish (NFE) AF: 0.666 AC: 45222 AN: 67892

Other (OTH) AF: 0.580 AC: 1219 AN: 2102

Alfa AF: 0.592 Hom.: 11471

Bravo AF: 0.544

Asia WGS AF: 0.639 AC: 2220 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.39
DANN	Benign	0.74
PhyloP100		-2.6
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: rs3788523; hg19: chr22-37269507;