rs746713

Positions:

• chr22-36863317-T-C
• chr22-36863317-T-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.33-728T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 151,564 control chromosomes in the GnomAD database, including 7,127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency: Genomes: 𝑓 0.31 (7127 hom., cov: 28)
• Consequence: NCF4 NM_000631.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.284

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=-0.89).
• BP6: Variant 22-36863317-T-C is Benign according to our data. Variant chr22-36863317-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCF4	NM_000631.5	c.33-728T>C		intron_variant		ENST00000248899.11	NP_000622.2
NCF4-AS1	NR_147197.1	n.351+6776A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCF4	ENST00000248899.11	c.33-728T>C		intron_variant		1	NM_000631.5	ENSP00000248899	P1
NCF4-AS1	ENST00000619915.1	n.349+6776A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46225 AN: 151444 Hom.: 7119 Cov.: 28

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.322

Gnomad SAS AF: 0.383

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.296

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

GnomAD4 genome AF: 0.305 AC: 46256 AN: 151564 Hom.: 7127 Cov.: 28 AF XY: 0.306 AC XY: 22675 AN XY: 73996

Gnomad4 AFR AF: 0.321

Gnomad4 AMR AF: 0.243

Gnomad4 ASJ AF: 0.322

Gnomad4 EAS AF: 0.322

Gnomad4 SAS AF: 0.381

Gnomad4 FIN AF: 0.313

Gnomad4 NFE AF: 0.302

Gnomad4 OTH AF: 0.302

Alfa AF: 0.288 Hom.: 8481

Bravo AF: 0.296

Asia WGS AF: 0.405 AC: 1407 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.9
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs746713; hg19: chr22-37259359;