22-36875840-T-C

Variant names:

• chr22-36875840-T-C
• rs2075939
• ENST00000397147.7:c.815T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_013416.4(NCF4):​c.815T>C​(p.Leu272Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.831 in 1,614,022 control chromosomes in the GnomAD database, including 558,514 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L272Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.86 (56740 hom., cov: 31)
  • Exomes 𝑓: 0.83 (501774 hom.)
• Consequence: NCF4 NM_013416.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.298

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1522777E-6).
• BP6: Variant 22-36875840-T-C is Benign according to our data. Variant chr22-36875840-T-C is described in ClinVar as [Benign]. Clinvar id is 260308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36875840-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.938 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCF4	NM_000631.5	c.758+57T>C		intron_variant	Intron 8 of 9	ENST00000248899.11	NP_000622.2
NCF4	NM_013416.4	c.815T>C	p.Leu272Pro	missense_variant	Exon 8 of 9		NP_038202.2
NCF4	XM_047441384.1	c.932+57T>C		intron_variant	Intron 9 of 10		XP_047297340.1
NCF4	XM_047441385.1	c.902+57T>C		intron_variant	Intron 9 of 10		XP_047297341.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCF4	ENST00000248899.11	c.758+57T>C		intron_variant	Intron 8 of 9	1	NM_000631.5	ENSP00000248899.6

Frequencies

GnomAD3 genomes AF: 0.861 AC: 130923 AN: 152054 Hom.: 56674 Cov.: 31

Gnomad AFR AF: 0.946

Gnomad AMI AF: 0.765

Gnomad AMR AF: 0.866

Gnomad ASJ AF: 0.862

Gnomad EAS AF: 0.673

Gnomad SAS AF: 0.797

Gnomad FIN AF: 0.835

Gnomad MID AF: 0.823

Gnomad NFE AF: 0.832

Gnomad OTH AF: 0.858

GnomAD3 exomes AF: 0.831 AC: 208985 AN: 251444 Hom.: 87262 AF XY: 0.828 AC XY: 112576 AN XY: 135894

Gnomad AFR exome AF: 0.948

Gnomad AMR exome AF: 0.859

Gnomad ASJ exome AF: 0.859

Gnomad EAS exome AF: 0.662

Gnomad SAS exome AF: 0.819

Gnomad FIN exome AF: 0.837

Gnomad NFE exome AF: 0.833

Gnomad OTH exome AF: 0.833

GnomAD4 exome AF: 0.828 AC: 1210107 AN: 1461850 Hom.: 501774 Cov.: 85 AF XY: 0.828 AC XY: 601888 AN XY: 727228

Gnomad4 AFR exome AF: 0.952

Gnomad4 AMR exome AF: 0.861

Gnomad4 ASJ exome AF: 0.855

Gnomad4 EAS exome AF: 0.692

Gnomad4 SAS exome AF: 0.816

Gnomad4 FIN exome AF: 0.844

Gnomad4 NFE exome AF: 0.826

Gnomad4 OTH exome AF: 0.839

GnomAD4 genome AF: 0.861 AC: 131046 AN: 152172 Hom.: 56740 Cov.: 31 AF XY: 0.859 AC XY: 63932 AN XY: 74386

Gnomad4 AFR AF: 0.946

Gnomad4 AMR AF: 0.867

Gnomad4 ASJ AF: 0.862

Gnomad4 EAS AF: 0.672

Gnomad4 SAS AF: 0.798

Gnomad4 FIN AF: 0.835

Gnomad4 NFE AF: 0.832

Gnomad4 OTH AF: 0.857

Alfa AF: 0.851 Hom.: 35601

Bravo AF: 0.866

TwinsUK AF: 0.836 AC: 3100

ALSPAC AF: 0.835 AC: 3217

ESP6500AA AF: 0.938 AC: 4132

ESP6500EA AF: 0.835 AC: 7184

ExAC AF: 0.834 AC: 101201

Asia WGS AF: 0.799 AC: 2779 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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 96% of patients studied by a panel of primary immunodeficiencies. Number of patients: 91. Only high quality variants are reported. -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Sep 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 Benign:2

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.047
DANN	Benign	0.96
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.000090	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-0.96	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.12
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Vest4		0.036
MPC		0.73
ClinPred		0.011	T
GERP RS		-0.74
gMVP		0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs2075939; hg19: chr22-37271882; COSMIC: COSV50620697; COSMIC: COSV50620697;