22-36868788-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000631.5(NCF4):c.342+1326A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0796 in 152,154 control chromosomes in the GnomAD database, including 507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency: Genomes: 𝑓 0.080 (507 hom., cov: 32)
• Consequence: NCF4 NM_000631.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.934

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 22-36868788-A-G is Benign according to our data. Variant chr22-36868788-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.087 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCF4	NM_000631.5	c.342+1326A>G		intron_variant		ENST00000248899.11
NCF4-AS1	NR_147197.1	n.351+1305T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCF4	ENST00000248899.11	c.342+1326A>G		intron_variant		1	NM_000631.5	P1
NCF4-AS1	ENST00000619915.1	n.349+1305T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0797 AC: 12112 AN: 152036 Hom.: 502 Cov.: 32

Gnomad AFR AF: 0.0718

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.0644

Gnomad ASJ AF: 0.0888

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.0567

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.0888

Gnomad OTH AF: 0.0940

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

GnomAD4 genome AF: 0.0796 AC: 12118 AN: 152154 Hom.: 507 Cov.: 32 AF XY: 0.0792 AC XY: 5891 AN XY: 74374

Gnomad4 AFR AF: 0.0717

Gnomad4 AMR AF: 0.0643

Gnomad4 ASJ AF: 0.0888

Gnomad4 EAS AF: 0.00290

Gnomad4 SAS AF: 0.0576

Gnomad4 FIN AF: 0.108

Gnomad4 NFE AF: 0.0889

Gnomad4 OTH AF: 0.0925

Alfa AF: 0.0511 Hom.: 77

Bravo AF: 0.0767

Asia WGS AF: 0.0410 AC: 143 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
Cadd	Benign	0.015
Dann	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17811059; hg19: chr22-37264830;