rs11552115

Variant names:

• chr22-36877700-G-A
• rs11552115
• NM_000631.5:c.897G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000631.5(NCF4):​c.897G>A​(p.Ser299Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0828 in 1,613,982 control chromosomes in the GnomAD database, including 7,021 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1462 hom., cov: 32)
  • Exomes 𝑓: 0.079 (5559 hom.)
• Consequence: NCF4 NM_000631.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.07
• Publications: 9 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 22-36877700-G-A is Benign according to our data. Variant chr22-36877700-G-A is described in ClinVar as Benign. ClinVar VariationId is 260303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.219 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCF4	NM_000631.5	MANE Select	c.897G>A	p.Ser299Ser	synonymous	Exon 10 of 10	NP_000622.2
	NCF4	NM_013416.4		c.*95G>A		3_prime_UTR	Exon 9 of 9	NP_038202.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCF4	ENST00000248899.11	TSL:1 MANE Select	c.897G>A	p.Ser299Ser	synonymous	Exon 10 of 10	ENSP00000248899.6
	NCF4	ENST00000397147.7	TSL:1	c.*95G>A		3_prime_UTR	Exon 9 of 9	ENSP00000380334.4
	NCF4	ENST00000650698.1		c.588G>A	p.Ser196Ser	synonymous	Exon 10 of 10	ENSP00000498381.1

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18189 AN: 152008 Hom.: 1458 Cov.: 32

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.0922

Gnomad EAS AF: 0.0538

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0572

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0682

Gnomad OTH AF: 0.115

GnomAD2 exomes AF: 0.0963 AC: 24197 AN: 251340 AF XY: 0.0926

Gnomad AFR exome AF: 0.229

Gnomad AMR exome AF: 0.175

Gnomad ASJ exome AF: 0.0877

Gnomad EAS exome AF: 0.0531

Gnomad FIN exome AF: 0.0587

Gnomad NFE exome AF: 0.0663

Gnomad OTH exome AF: 0.0808

GnomAD4 exome AF: 0.0790 AC: 115424 AN: 1461856 Hom.: 5559 Cov.: 31 AF XY: 0.0792 AC XY: 57611 AN XY: 727230

African (AFR) AF: 0.233 AC: 7796 AN: 33480

American (AMR) AF: 0.171 AC: 7646 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0853 AC: 2229 AN: 26136

East Asian (EAS) AF: 0.0457 AC: 1814 AN: 39692

South Asian (SAS) AF: 0.108 AC: 9327 AN: 86254

European-Finnish (FIN) AF: 0.0584 AC: 3120 AN: 53418

Middle Eastern (MID) AF: 0.0926 AC: 534 AN: 5768

European-Non Finnish (NFE) AF: 0.0697 AC: 77505 AN: 1111988

Other (OTH) AF: 0.0903 AC: 5453 AN: 60396

GnomAD4 genome AF: 0.120 AC: 18228 AN: 152126 Hom.: 1462 Cov.: 32 AF XY: 0.120 AC XY: 8902 AN XY: 74394

African (AFR) AF: 0.223 AC: 9247 AN: 41434

American (AMR) AF: 0.151 AC: 2314 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0922 AC: 320 AN: 3470

East Asian (EAS) AF: 0.0533 AC: 276 AN: 5176

South Asian (SAS) AF: 0.107 AC: 515 AN: 4816

European-Finnish (FIN) AF: 0.0572 AC: 607 AN: 10612

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0683 AC: 4642 AN: 68010

Other (OTH) AF: 0.115 AC: 242 AN: 2112

Alfa AF: 0.0918 Hom.: 410

Bravo AF: 0.132

Asia WGS AF: 0.0850 AC: 296 AN: 3478

EpiCase AF: 0.0707

EpiControl AF: 0.0702

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.063
DANN	Benign	0.71
PhyloP100		-4.1
Mutation Taster		=95/5	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: rs11552115; hg19: chr22-37273742;