NM_000631.5:c.343-135A>G

Variant names:

• chr22-36870280-A-G
• rs2075938
• NM_000631.5:c.343-135A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000631.5(NCF4):​c.343-135A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.699 in 1,263,548 control chromosomes in the GnomAD database, including 310,452 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33471 hom., cov: 32)
  • Exomes 𝑓: 0.70 (276981 hom.)
• Consequence: NCF4 NM_000631.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.840
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 22-36870280-A-G is Benign according to our data. Variant chr22-36870280-A-G is described in ClinVar as Benign. ClinVar VariationId is 1236515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCF4	NM_000631.5	c.343-135A>G		intron_variant	Intron 4 of 9	ENST00000248899.11	NP_000622.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCF4	ENST00000248899.11	c.343-135A>G		intron_variant	Intron 4 of 9	1	NM_000631.5	ENSP00000248899.6

Frequencies

GnomAD3 genomes AF: 0.658 AC: 99969 AN: 151948 Hom.: 33444 Cov.: 32

Gnomad AFR AF: 0.538

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.675

Gnomad ASJ AF: 0.759

Gnomad EAS AF: 0.643

Gnomad SAS AF: 0.668

Gnomad FIN AF: 0.705

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.717

Gnomad OTH AF: 0.658

GnomAD4 exome AF: 0.704 AC: 782856 AN: 1111482 Hom.: 276981 Cov.: 15 AF XY: 0.704 AC XY: 398835 AN XY: 566356

African (AFR) AF: 0.522 AC: 13920 AN: 26648

American (AMR) AF: 0.659 AC: 27549 AN: 41782

Ashkenazi Jewish (ASJ) AF: 0.754 AC: 17869 AN: 23684

East Asian (EAS) AF: 0.678 AC: 25487 AN: 37608

South Asian (SAS) AF: 0.680 AC: 52710 AN: 77544

European-Finnish (FIN) AF: 0.727 AC: 28832 AN: 39682

Middle Eastern (MID) AF: 0.570 AC: 2616 AN: 4586

European-Non Finnish (NFE) AF: 0.715 AC: 579819 AN: 810946

Other (OTH) AF: 0.695 AC: 34054 AN: 49002

GnomAD4 genome AF: 0.658 AC: 100040 AN: 152066 Hom.: 33471 Cov.: 32 AF XY: 0.658 AC XY: 48881 AN XY: 74330

African (AFR) AF: 0.538 AC: 22308 AN: 41466

American (AMR) AF: 0.675 AC: 10310 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.759 AC: 2632 AN: 3470

East Asian (EAS) AF: 0.643 AC: 3324 AN: 5170

South Asian (SAS) AF: 0.667 AC: 3210 AN: 4812

European-Finnish (FIN) AF: 0.705 AC: 7458 AN: 10586

Middle Eastern (MID) AF: 0.565 AC: 166 AN: 294

European-Non Finnish (NFE) AF: 0.717 AC: 48717 AN: 67976

Other (OTH) AF: 0.659 AC: 1391 AN: 2110

Alfa AF: 0.692 Hom.: 8166

Bravo AF: 0.647

Asia WGS AF: 0.677 AC: 2354 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.42
DANN	Benign	0.32
PhyloP100		-0.84
Mutation Taster		=100/0	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: rs2075938; hg19: chr22-37266322;