ENST00000431290.2:n.395-2561C>T

Variant names:

• chr22-36860804-G-A
• rs1883112
• ENST00000431290.2:n.395-2561C>T

Variant summary

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

The ENST00000431290.2(NCF4-AS1):​n.395-2561C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 151,916 control chromosomes in the GnomAD database, including 13,554 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 0.40 (13554 hom., cov: 31)
• Consequence: NCF4-AS1 ENST00000431290.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.793
• Publications: 64 publications found

Genes affected

NCF4-AS1 (HGNC:40393): (NCF4 antisense RNA 1)

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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.646 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCF4-AS1	NR_147197.1	n.351+9289C>T		intron_variant	Intron 1 of 1
NCF4	NM_000631.5	c.-368G>A		upstream_gene_variant		ENST00000248899.11	NP_000622.2
NCF4	NM_013416.4	c.-368G>A		upstream_gene_variant			NP_038202.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCF4	ENST00000248899.11	c.-368G>A		upstream_gene_variant		1	NM_000631.5	ENSP00000248899.6

Frequencies

GnomAD3 genomes AF: 0.395 AC: 59998 AN: 151796 Hom.: 13538 Cov.: 31

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.264

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.400

Gnomad EAS AF: 0.664

Gnomad SAS AF: 0.482

Gnomad FIN AF: 0.619

Gnomad MID AF: 0.290

Gnomad NFE AF: 0.447

Gnomad OTH AF: 0.384

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

GnomAD4 genome AF: 0.395 AC: 60026 AN: 151916 Hom.: 13554 Cov.: 31 AF XY: 0.407 AC XY: 30190 AN XY: 74232

African (AFR) AF: 0.180 AC: 7448 AN: 41466

American (AMR) AF: 0.485 AC: 7406 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 1386 AN: 3468

East Asian (EAS) AF: 0.664 AC: 3427 AN: 5160

South Asian (SAS) AF: 0.483 AC: 2323 AN: 4806

European-Finnish (FIN) AF: 0.619 AC: 6517 AN: 10528

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.447 AC: 30386 AN: 67908

Other (OTH) AF: 0.382 AC: 804 AN: 2106

Alfa AF: 0.426 Hom.: 31070

Bravo AF: 0.378

Asia WGS AF: 0.536 AC: 1864 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 08, 2018

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	-0.81
CADD	Benign	12
DANN	Benign	0.92
PhyloP100		0.79
PromoterAI		0.0065	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1883112; hg19: chr22-37256846;