rs35012521

chr1-183563229-T-Achr1-183563229-T-C

Variant summary

Our verdict is Benign. Variant got -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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N419Y) has been classified as 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:9
• Conservation: PhyloP100: 2.63

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 281211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-183563229-T-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCF2	NM_000433.4	c.1256A>T	p.Asn419Ile	missense_variant	13/15	ENST00000367535.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCF2	ENST00000367535.8	c.1256A>T	p.Asn419Ile	missense_variant	13/15	1	NM_000433.4	P1

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

GnomAD3 exomes AF: 0.00552 AC: 1387 AN: 251352 Hom.: 6 AF XY: 0.00573 AC XY: 778 AN XY: 135834

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 SAS exome AF: 0.0105

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

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.00449

Gnomad4 ASJ exome AF: 0.00570

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0106

Gnomad4 FIN exome AF: 0.00161

Gnomad4 NFE exome AF: 0.00898

Gnomad4 OTH exome AF: 0.00952

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

Gnomad4 AFR AF: 0.00174

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00973

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00849

Gnomad4 OTH AF: 0.00759

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

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 05, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 17, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	NCF2: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 13, 2020	This variant is associated with the following publications: (PMID: 23821607, 16937026, 27884173, 26764160, 27535533, 29454792, 24931457) -

Developmental and epileptic encephalopathy, 28 Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

-

The homozygous p.Asn419Ile variant in NCF2 has been identified in a Tunisian individual with chronic granulomatous disease (PMID: 16937026), individuals without chronic granulomatous disease (PMID: 23821607), and has been identified in >1% of South Asian chromosomes and 6 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive chronic granulomatous disease. -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	D;D;.;D
MetaRNN	Benign	0.010	T;T;T;T
MetaSVM	Benign	-0.74	T
MutationTaster	Benign	0.52	D;N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-4.3	D;D;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.99	.;.;D;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

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

Publications

LitVar

Other links and lift over

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