rs150103256

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000631.5(NCF4):c.478G>A(p.Val160Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,570,010 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 8 hom. )

Consequence

NCF4
NM_000631.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.0690

Variant links:

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 links:

NCF4 (HGNC:):

NCF4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003737539).

BP6

Variant 22-36871659-G-A is Benign according to our data. Variant chr22-36871659-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 341554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36871659-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00123 (187/152366) while in subpopulation SAS AF= 0.0101 (49/4834). AF 95% confidence interval is 0.00788. There are 3 homozygotes in gnomad4. There are 101 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCF4	NM_000631.5 linkuse as main transcript	c.478G>A	p.Val160Met	missense_variant	6/10	ENST00000248899.11	NP_000622.2	Q15080-1
NCF4	NM_013416.4 linkuse as main transcript	c.478G>A	p.Val160Met	missense_variant	6/9		NP_038202.2	Q15080-3
NCF4	XM_047441384.1 linkuse as main transcript	c.652G>A	p.Val218Met	missense_variant	7/11		XP_047297340.1
NCF4	XM_047441385.1 linkuse as main transcript	c.622G>A	p.Val208Met	missense_variant	7/11		XP_047297341.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCF4	ENST00000248899.11 linkuse as main transcript	c.478G>A	p.Val160Met	missense_variant	6/10	1	NM_000631.5	ENSP00000248899.6		Q15080-1

Frequencies

GnomAD3 genomes

AF:

0.00123

AC:

187

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00269

Gnomad SAS

AF:

0.0101

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000941

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00176

AC:

324

AN:

184276

Hom.:

AF XY:

0.00194

AC XY:

190

AN XY:

98110

show subpopulations

Gnomad AFR exome

AF:

0.000632

Gnomad AMR exome

AF:

0.000362

Gnomad ASJ exome

AF:

0.00282

Gnomad EAS exome

AF:

0.00212

Gnomad SAS exome

AF:

0.00766

Gnomad FIN exome

AF:

0.0000599

Gnomad NFE exome

AF:

0.000705

Gnomad OTH exome

AF:

0.00205

GnomAD4 exome

AF:

0.00112

AC:

1587

AN:

1417644

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

907

AN XY:

700982

show subpopulations

Gnomad4 AFR exome

AF:

0.000246

Gnomad4 AMR exome

AF:

0.000366

Gnomad4 ASJ exome

AF:

0.00335

Gnomad4 EAS exome

AF:

0.00324

Gnomad4 SAS exome

AF:

0.00682

Gnomad4 FIN exome

AF:

0.0000796

Gnomad4 NFE exome

AF:

0.000593

Gnomad4 OTH exome

AF:

0.00230

GnomAD4 genome

AF:

0.00123

AC:

187

AN:

152366

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

101

AN XY:

74522

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00270

Gnomad4 SAS

AF:

0.0101

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000941

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00114

Hom.:

Bravo

AF:

0.000948

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00137

AC:

ESP6500EA

AF:

0.000584

AC:

ExAC

AF:

0.00141

AC:

168

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 26, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

NCF4-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 26, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.65

CADD

Benign

9.2

DANN

Benign

0.84

DEOGEN2

Benign

0.024

T;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.48

T;T;T

MetaRNN

Benign

0.0037

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.20

.;N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.50

N;N;N

REVEL

Benign

0.017

Sift

Benign

0.21

T;T;T

Sift4G

Benign

0.24

T;T;T

Polyphen

0.12

.;B;.

Vest4

0.12, 0.10

MVP

0.53

MPC

0.18

ClinPred

0.0011

GERP RS

-1.7

Varity_R

0.016

gMVP

0.28

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over