Genetic Variant NM_000631.5:c.69G>A (chr22-36864081-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -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 (★★). Synonymous variant affecting the same amino acid position (i.e. S23S) has been classified as Likely 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

Publications

9 publications found

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

NCF4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 260306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000631.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NCF4	NM_000631.5	MANE Select	c.69G>A	p.Ser23Ser	synonymous	Exon 2 of 10	NP_000622.2
NCF4	NM_013416.4		c.69G>A	p.Ser23Ser	synonymous	Exon 2 of 9	NP_038202.2	Q15080-3
NCF4-AS1	NR_147197.1		n.351+6012C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NCF4	ENST00000248899.11	TSL:1 MANE Select	c.69G>A	p.Ser23Ser	synonymous	Exon 2 of 10	ENSP00000248899.6	Q15080-1
NCF4	ENST00000397147.7	TSL:1	c.69G>A	p.Ser23Ser	synonymous	Exon 2 of 9	ENSP00000380334.4	Q15080-3
NCF4	ENST00000650698.1		c.-241G>A		5_prime_UTR	Exon 2 of 10	ENSP00000498381.1	A0A494BZS1

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

GnomAD2 exomes

AF:

0.0412

AC:

10371

AN:

251492

AF XY:

0.0325

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 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

African (AFR)

AF:

0.211

AC:

7066

AN:

33466

American (AMR)

AF:

0.138

AC:

6172

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00352

AC:

AN:

26136

East Asian (EAS)

AF:

0.0663

AC:

2633

AN:

39696

South Asian (SAS)

AF:

0.0123

AC:

1062

AN:

86258

European-Finnish (FIN)

AF:

0.000168

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.0125

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000984

AC:

1094

AN:

1111996

Other (OTH)

AF:

0.0227

AC:

1372

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1245

2490

3734

4979

6224

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

364

728

1092

1456

1820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0688

AC:

10465

AN:

152094

Hom.:

938

Cov.:

AF XY:

0.0681

AC XY:

5063

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.202

AC:

8388

AN:

41432

American (AMR)

AF:

0.0936

AC:

1431

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3472

East Asian (EAS)

AF:

0.0615

AC:

319

AN:

5184

South Asian (SAS)

AF:

0.0179

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00149

AC:

101

AN:

68002

Other (OTH)

AF:

0.0520

AC:

110

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

429

859

1288

1718

2147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

288

384

480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0586

Hom.:

619

Bravo

AF:

0.0837

Asia WGS

AF:

0.0550

AC:

192

AN:

3478

EpiCase

AF:

0.00169

EpiControl

AF:

0.00284

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 (1)

NCF4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

1.5

(source)

DANN

Benign

0.84

PhyloP100

-0.41

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over