chr1-183590569-A-C

Variant names:

• chr1-183590569-A-C
• rs2274065
• ENST00000367536.5:c.-30-210T>G

Variant summary

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

The ENST00000367536.5(NCF2):​c.-30-210T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 585,042 control chromosomes in the GnomAD database, including 7,557 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (4548 hom., cov: 32)
  • Exomes 𝑓: 0.094 (3009 hom.)
• Consequence: NCF2 ENST00000367536.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.201
• Publications: 17 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 (BayesDel_noAF=-0.83).
• BP6: Variant 1-183590569-A-C is Benign according to our data. Variant chr1-183590569-A-C is described in ClinVar as Benign. ClinVar VariationId is 294087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.431 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCF2	NM_000433.4	c.-240T>G		upstream_gene_variant		ENST00000367535.8	NP_000424.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCF2	ENST00000367535.8	c.-240T>G		upstream_gene_variant		1	NM_000433.4	ENSP00000356505.4

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28587 AN: 151664 Hom.: 4540 Cov.: 32

Gnomad AFR AF: 0.437

Gnomad AMI AF: 0.142

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.0761

Gnomad EAS AF: 0.0757

Gnomad SAS AF: 0.0706

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0741

Gnomad OTH AF: 0.160

GnomAD4 exome AF: 0.0940 AC: 40734 AN: 433260 Hom.: 3009 Cov.: 3 AF XY: 0.0900 AC XY: 20796 AN XY: 231168

African (AFR) AF: 0.432 AC: 5352 AN: 12378

American (AMR) AF: 0.210 AC: 4740 AN: 22518

Ashkenazi Jewish (ASJ) AF: 0.0800 AC: 1099 AN: 13746

East Asian (EAS) AF: 0.0847 AC: 2336 AN: 27578

South Asian (SAS) AF: 0.0720 AC: 3554 AN: 49330

European-Finnish (FIN) AF: 0.0938 AC: 2438 AN: 25996

Middle Eastern (MID) AF: 0.0868 AC: 166 AN: 1912

European-Non Finnish (NFE) AF: 0.0718 AC: 18335 AN: 255232

Other (OTH) AF: 0.110 AC: 2714 AN: 24570

GnomAD4 genome AF: 0.189 AC: 28642 AN: 151782 Hom.: 4548 Cov.: 32 AF XY: 0.187 AC XY: 13879 AN XY: 74134

African (AFR) AF: 0.437 AC: 18090 AN: 41434

American (AMR) AF: 0.194 AC: 2971 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0761 AC: 264 AN: 3470

East Asian (EAS) AF: 0.0757 AC: 392 AN: 5180

South Asian (SAS) AF: 0.0709 AC: 342 AN: 4824

European-Finnish (FIN) AF: 0.102 AC: 1052 AN: 10292

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0742 AC: 5042 AN: 67976

Other (OTH) AF: 0.158 AC: 334 AN: 2108

Alfa AF: 0.101 Hom.: 2700

Bravo AF: 0.208

Asia WGS AF: 0.0940 AC: 327 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Sep 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.1
DANN	Benign	0.82
PhyloP100		0.20
PromoterAI		0.38	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs2274065; hg19: chr1-183559704;