rs2072711

Variant names:

• chr22-36872513-A-G
• rs2072711
• NM_000631.5:c.627+88A>G

Your query was ambiguous. Multiple possible variants found:

• chr22-36872513-A-G
• chr22-36872513-A-T

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.627+88A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.835 in 1,152,614 control chromosomes in the GnomAD database, including 402,369 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (56218 hom., cov: 27)
  • Exomes 𝑓: 0.83 (346151 hom.)
• Consequence: NCF4 NM_000631.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.829
• Publications: 19 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=-0.92).
• BP6: Variant 22-36872513-A-G is Benign according to our data. Variant chr22-36872513-A-G is described in ClinVar as Benign. ClinVar VariationId is 1289546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.937 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCF4	NM_000631.5	c.627+88A>G		intron_variant	Intron 7 of 9	ENST00000248899.11	NP_000622.2
NCF4	NM_013416.4	c.627+88A>G		intron_variant	Intron 7 of 8		NP_038202.2
NCF4	XM_047441384.1	c.801+88A>G		intron_variant	Intron 8 of 10		XP_047297340.1
NCF4	XM_047441385.1	c.771+88A>G		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+88A>G		intron_variant	Intron 7 of 9	1	NM_000631.5	ENSP00000248899.6

Frequencies

GnomAD3 genomes AF: 0.861 AC: 129932 AN: 150942 Hom.: 56151 Cov.: 27

Gnomad AFR AF: 0.945

Gnomad AMI AF: 0.765

Gnomad AMR AF: 0.867

Gnomad ASJ AF: 0.863

Gnomad EAS AF: 0.677

Gnomad SAS AF: 0.798

Gnomad FIN AF: 0.834

Gnomad MID AF: 0.823

Gnomad NFE AF: 0.832

Gnomad OTH AF: 0.860

GnomAD4 exome AF: 0.831 AC: 831906 AN: 1001554 Hom.: 346151 AF XY: 0.830 AC XY: 426989 AN XY: 514530

African (AFR) AF: 0.949 AC: 23581 AN: 24836

American (AMR) AF: 0.862 AC: 33863 AN: 39294

Ashkenazi Jewish (ASJ) AF: 0.857 AC: 19647 AN: 22932

East Asian (EAS) AF: 0.711 AC: 26307 AN: 37002

South Asian (SAS) AF: 0.818 AC: 61388 AN: 75062

European-Finnish (FIN) AF: 0.845 AC: 40822 AN: 48314

Middle Eastern (MID) AF: 0.831 AC: 3753 AN: 4518

European-Non Finnish (NFE) AF: 0.830 AC: 584231 AN: 704108

Other (OTH) AF: 0.842 AC: 38314 AN: 45488

GnomAD4 genome AF: 0.861 AC: 130057 AN: 151060 Hom.: 56218 Cov.: 27 AF XY: 0.860 AC XY: 63414 AN XY: 73766

African (AFR) AF: 0.945 AC: 38959 AN: 41230

American (AMR) AF: 0.867 AC: 13177 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.863 AC: 2989 AN: 3464

East Asian (EAS) AF: 0.677 AC: 3435 AN: 5074

South Asian (SAS) AF: 0.798 AC: 3801 AN: 4764

European-Finnish (FIN) AF: 0.834 AC: 8703 AN: 10430

Middle Eastern (MID) AF: 0.834 AC: 242 AN: 290

European-Non Finnish (NFE) AF: 0.832 AC: 56257 AN: 67614

Other (OTH) AF: 0.860 AC: 1810 AN: 2104

Alfa AF: 0.842 Hom.: 178198

Bravo AF: 0.866

Asia WGS AF: 0.798 AC: 2772 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 63% of patients studied by a panel of primary immunodeficiencies. Number of patients: 60. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.53
DANN	Benign	0.57
PhyloP100		-0.83
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: rs2072711; hg19: chr22-37268555;