NM_000433.4:c.890T>C

Variant names:

• chr1-183566954-A-G
• rs35937854
• NM_000433.4:c.890T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000433.4(NCF2):​c.890T>C​(p.Val297Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00224 in 1,614,150 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V297V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (27 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (25 hom.)
• Consequence: NCF2 NM_000433.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.32
• Publications: 11 publications found

Genes affected

NCF2 (HGNC:7661): (neutrophil cytosolic factor 2) This gene encodes neutrophil cytosolic factor 2, the 67-kilodalton cytosolic subunit of the multi-protein NADPH oxidase complex found in neutrophils. This oxidase produces a burst of superoxide which is delivered to the lumen of the neutrophil phagosome. Mutations in this gene, as well as in other NADPH oxidase subunits, can result in chronic granulomatous disease, a disease that causes recurrent infections by catalase-positive organisms. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jun 2010]

SMG7 (HGNC:16792): (SMG7 nonsense mediated mRNA decay factor) This gene encodes a protein that is essential for nonsense-mediated mRNA decay (NMD); a process whereby transcripts with premature termination codons are targeted for rapid degradation by a mRNA decay complex. The mRNA decay complex consists, in part, of this protein along with proteins SMG5 and UPF1. The N-terminal domain of this protein is thought to mediate its association with SMG5 or UPF1 while the C-terminal domain interacts with the mRNA decay complex. This protein may therefore couple changes in UPF1 phosphorylation state to the degradation of NMD-candidate transcripts. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Aug 2011]

SMG7 Gene-Disease associations (from GenCC):

• autoimmune disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030933917).
• BP6: Variant 1-183566954-A-G is Benign according to our data. Variant chr1-183566954-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 281319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0119 (1806/152290) while in subpopulation AFR AF = 0.0409 (1700/41548). AF 95% confidence interval is 0.0393. There are 27 homozygotes in GnomAd4. There are 847 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000433.4. 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
	NCF2	NM_000433.4	MANE Select	c.890T>C	p.Val297Ala	missense	Exon 9 of 15	NP_000424.2	P19878-1
	NCF2	NM_001127651.3		c.890T>C	p.Val297Ala	missense	Exon 10 of 16	NP_001121123.1	P19878-1
	NCF2	NM_001410895.1		c.782T>C	p.Val261Ala	missense	Exon 9 of 15	NP_001397824.1	A0A8V8TMB9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCF2	ENST00000367535.8	TSL:1 MANE Select	c.890T>C	p.Val297Ala	missense	Exon 9 of 15	ENSP00000356505.4	P19878-1
	NCF2	ENST00000367536.5	TSL:1	c.890T>C	p.Val297Ala	missense	Exon 10 of 16	ENSP00000356506.1	P19878-1
	NCF2	ENST00000946295.1		c.890T>C	p.Val297Ala	missense	Exon 9 of 16	ENSP00000616354.1

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1805 AN: 152172 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00311 AC: 781 AN: 251474 AF XY: 0.00235

Gnomad AFR exome AF: 0.0417

Gnomad AMR exome AF: 0.00228

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00124 AC: 1813 AN: 1461860 Hom.: 25 Cov.: 32 AF XY: 0.00108 AC XY: 787 AN XY: 727234

African (AFR) AF: 0.0435 AC: 1458 AN: 33480

American (AMR) AF: 0.00255 AC: 114 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86254

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

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5746

European-Non Finnish (NFE) AF: 0.0000450 AC: 50 AN: 1112012

Other (OTH) AF: 0.00288 AC: 174 AN: 60390

GnomAD4 genome AF: 0.0119 AC: 1806 AN: 152290 Hom.: 27 Cov.: 32 AF XY: 0.0114 AC XY: 847 AN XY: 74470

African (AFR) AF: 0.0409 AC: 1700 AN: 41548

American (AMR) AF: 0.00523 AC: 80 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68028

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.00476 Hom.: 22

Bravo AF: 0.0137

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0381 AC: 168

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00372 AC: 452

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.10	N
PhyloP100		4.3
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.046
Sift	Benign	0.22	T
Sift4G	Uncertain	0.057	T
Polyphen		0.0020	B
Vest4		0.23
MVP		0.43
MPC		0.38
ClinPred		0.027	T
GERP RS		3.8
Varity_R		0.090
gMVP		0.36
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs35937854; hg19: chr1-183536089;