rs10854695

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000631.5(NCF4):c.69G>A(p.Ser23Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,613,954 control chromosomes in the GnomAD database, including 2,314 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.069 ( 938 hom., cov: 31)

Exomes 𝑓: 0.013 ( 1376 hom. )

Consequence

NCF4
NM_000631.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.406

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 22-36864081-G-A is Benign according to our data. Variant chr22-36864081-G-A is described in ClinVar as [Benign]. Clinvar id is 260306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36864081-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.406 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCF4	NM_000631.5 linkuse as main transcript	c.69G>A	p.Ser23Ser	synonymous_variant	2/10	ENST00000248899.11	NP_000622.2	Q15080-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCF4	ENST00000248899.11 linkuse as main transcript	c.69G>A	p.Ser23Ser	synonymous_variant	2/10	1	NM_000631.5	ENSP00000248899.6		Q15080-1

Frequencies

GnomAD3 genomes

AF:

0.0687

AC:

10440

AN:

151976

Hom.:

935

Cov.:

show subpopulations

Gnomad AFR

AF:

0.203

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0933

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.0622

Gnomad SAS

AF:

0.0179

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00149

Gnomad OTH

AF:

0.0516

GnomAD3 exomes

AF:

0.0412

AC:

10371

AN:

251492

Hom.:

787

AF XY:

0.0325

AC XY:

4414

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.210

Gnomad AMR exome

AF:

0.144

Gnomad ASJ exome

AF:

0.00456

Gnomad EAS exome

AF:

0.0651

Gnomad SAS exome

AF:

0.0137

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00167

Gnomad OTH exome

AF:

0.0208

GnomAD4 exome

AF:

0.0134

AC:

19572

AN:

1461860

Hom.:

1376

Cov.:

AF XY:

0.0121

AC XY:

8788

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.211

Gnomad4 AMR exome

AF:

0.138

Gnomad4 ASJ exome

AF:

0.00352

Gnomad4 EAS exome

AF:

0.0663

Gnomad4 SAS exome

AF:

0.0123

Gnomad4 FIN exome

AF:

0.000168

Gnomad4 NFE exome

AF:

0.000984

Gnomad4 OTH exome

AF:

0.0227

GnomAD4 genome

AF:

0.0688

AC:

10465

AN:

152094

Hom.:

938

Cov.:

AF XY:

0.0681

AC XY:

5063

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.202

Gnomad4 AMR

AF:

0.0936

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.0615

Gnomad4 SAS

AF:

0.0179

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.00149

Gnomad4 OTH

AF:

0.0520

Alfa

AF:

0.0278

Hom.:

188

Bravo

AF:

0.0837

Asia WGS

AF:

0.0550

AC:

192

AN:

3478

EpiCase

AF:

0.00169

EpiControl

AF:

0.00284

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2018	- -
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

Feb 01, 2024

- -

NCF4-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 06, 2023

This variant is classified as 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

BayesDel_noAF

Benign

-0.56

CADD

Benign

1.5

DANN

Benign

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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