rs34373276

Variant names:

• chr22-36864075-C-T
• rs34373276
• NM_000631.5:c.63C>T

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.63C>T​(p.Ala21Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00489 in 1,614,132 control chromosomes in the GnomAD database, including 340 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (190 hom., cov: 30)
  • Exomes 𝑓: 0.0027 (150 hom.)
• Consequence: NCF4 NM_000631.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.242
• Publications: 3 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-AS1 (HGNC:40393): (NCF4 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 22-36864075-C-T is Benign according to our data. Variant chr22-36864075-C-T is described in ClinVar as Benign. ClinVar VariationId is 341548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.242 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0885 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.63C>T	p.Ala21Ala	synonymous	Exon 2 of 10	NP_000622.2
	NCF4	NM_013416.4		c.63C>T	p.Ala21Ala	synonymous	Exon 2 of 9	NP_038202.2	Q15080-3
	NCF4-AS1	NR_147197.1		n.351+6018G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCF4	ENST00000248899.11	TSL:1 MANE Select	c.63C>T	p.Ala21Ala	synonymous	Exon 2 of 10	ENSP00000248899.6	Q15080-1
	NCF4	ENST00000397147.7	TSL:1	c.63C>T	p.Ala21Ala	synonymous	Exon 2 of 9	ENSP00000380334.4	Q15080-3
	NCF4	ENST00000650698.1		c.-247C>T		5_prime_UTR	Exon 2 of 10	ENSP00000498381.1	A0A494BZS1

Frequencies

GnomAD3 genomes AF: 0.0262 AC: 3983 AN: 152146 Hom.: 189 Cov.: 30

Gnomad AFR AF: 0.0911

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00955

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0186

GnomAD2 exomes AF: 0.00669 AC: 1683 AN: 251496 AF XY: 0.00488

Gnomad AFR exome AF: 0.0915

Gnomad AMR exome AF: 0.00416

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00267 AC: 3902 AN: 1461868 Hom.: 150 Cov.: 31 AF XY: 0.00234 AC XY: 1703 AN XY: 727242

African (AFR) AF: 0.0941 AC: 3149 AN: 33472

American (AMR) AF: 0.00472 AC: 211 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.000145 AC: 161 AN: 1111996

Other (OTH) AF: 0.00586 AC: 354 AN: 60394

GnomAD4 genome AF: 0.0262 AC: 3987 AN: 152264 Hom.: 190 Cov.: 30 AF XY: 0.0257 AC XY: 1916 AN XY: 74464

African (AFR) AF: 0.0909 AC: 3776 AN: 41536

American (AMR) AF: 0.00954 AC: 146 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68020

Other (OTH) AF: 0.0184 AC: 39 AN: 2114

Alfa AF: 0.0151 Hom.: 70

Bravo AF: 0.0305

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.3
DANN	Benign	0.80
PhyloP100		-0.24
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34373276; hg19: chr22-37260117;