rs35012521

Variant names:

• chr1-183563229-T-A
• rs35012521
• NM_000433.4:c.1256A>T

Your query was ambiguous. Multiple possible variants found:

• chr1-183563229-T-A
• chr1-183563229-T-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.1256A>T​(p.Asn419Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00794 in 1,614,052 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts 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. N419N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0054 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (72 hom.)
• Consequence: NCF2 NM_000433.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.63
• Publications: 26 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=0.0100801885).
• BP6: Variant 1-183563229-T-A is Benign according to our data. Variant chr1-183563229-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 281211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00537 (817/152190) while in subpopulation SAS AF = 0.00973 (47/4828). AF 95% confidence interval is 0.00791. There are 6 homozygotes in GnomAd4. There are 374 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.1256A>T	p.Asn419Ile	missense	Exon 13 of 15	NP_000424.2	P19878-1
	NCF2	NM_001127651.3		c.1256A>T	p.Asn419Ile	missense	Exon 14 of 16	NP_001121123.1	P19878-1
	NCF2	NM_001410895.1		c.1148A>T	p.Asn383Ile	missense	Exon 13 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.1256A>T	p.Asn419Ile	missense	Exon 13 of 15	ENSP00000356505.4	P19878-1
	NCF2	ENST00000367536.5	TSL:1	c.1256A>T	p.Asn419Ile	missense	Exon 14 of 16	ENSP00000356506.1	P19878-1
	NCF2	ENST00000946295.1		c.1256A>T	p.Asn419Ile	missense	Exon 13 of 16	ENSP00000616354.1

Frequencies

GnomAD3 genomes AF: 0.00537 AC: 817 AN: 152072 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00973

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00848

Gnomad OTH AF: 0.00767

GnomAD2 exomes AF: 0.00552 AC: 1387 AN: 251352 AF XY: 0.00573

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00445

Gnomad ASJ exome AF: 0.00575

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00675

Gnomad OTH exome AF: 0.00653

GnomAD4 exome AF: 0.00821 AC: 12000 AN: 1461862 Hom.: 72 Cov.: 32 AF XY: 0.00819 AC XY: 5956 AN XY: 727234

African (AFR) AF: 0.000986 AC: 33 AN: 33480

American (AMR) AF: 0.00449 AC: 201 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00570 AC: 149 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0106 AC: 917 AN: 86258

European-Finnish (FIN) AF: 0.00161 AC: 86 AN: 53412

Middle Eastern (MID) AF: 0.00936 AC: 54 AN: 5768

European-Non Finnish (NFE) AF: 0.00898 AC: 9984 AN: 1111990

Other (OTH) AF: 0.00952 AC: 575 AN: 60396

GnomAD4 genome AF: 0.00537 AC: 817 AN: 152190 Hom.: 6 Cov.: 32 AF XY: 0.00503 AC XY: 374 AN XY: 74404

African (AFR) AF: 0.00174 AC: 72 AN: 41496

American (AMR) AF: 0.00451 AC: 69 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00973 AC: 47 AN: 4828

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10608

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00849 AC: 577 AN: 67998

Other (OTH) AF: 0.00759 AC: 16 AN: 2108

Alfa AF: 0.00677 Hom.: 3

Bravo AF: 0.00550

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.0127 AC: 49

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00872 AC: 75

ExAC AF: 0.00537 AC: 652

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.00905

EpiControl AF: 0.00812

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 (3)
-	-	3	not provided (3)
-	-	1	Developmental and epileptic encephalopathy, 28 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.6
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.28
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.46
MVP		0.70
MPC		0.80
ClinPred		0.034	T
GERP RS		4.5
Varity_R		0.89
gMVP		0.50
Mutation Taster		=82/18	polymorphism

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: rs35012521; hg19: chr1-183532364; COSMIC: COSV99055722; COSMIC: COSV99055722;