chr7-74779113-C-CA

Position:

• chr7-74779113-C-CA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000265.7(NCF1):​c.186dupA​(p.Gly63fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: NCF1 NM_000265.7 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -5.52

Genes affected

NCF1 (HGNC:7660): (neutrophil cytosolic factor 1) The protein encoded by this gene is a 47 kDa cytosolic subunit of neutrophil NADPH oxidase. This oxidase is a multicomponent enzyme that is activated to produce superoxide anion. Mutations in this gene have been associated with chronic granulomatous disease. [provided by RefSeq, Jul 2008]

NCF1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-74779113-C-CA is Pathogenic according to our data. Variant chr7-74779113-C-CA is described in ClinVar as [Pathogenic]. Clinvar id is 280629.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCF1	NM_000265.7	c.186dupA	p.Gly63fs	frameshift_variant	3/11	ENST00000289473.11	NP_000256.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCF1	ENST00000289473.11	c.186dupA	p.Gly63fs	frameshift_variant	3/11	1	NM_000265.7	ENSP00000289473.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 17

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 15, 2016

The c.186dupA variant in the NCF1 gene has not been reported previously as a pathogenic variantnor as a benign variant, to our knowledge. The c.186dupA variant causes a frameshift starting withcodon Glycine 63, changes this amino acid to an Arginine residue, and creates a premature Stop codonat position 20 of the new reading frame, denoted p.Gly63ArgfsX20. This variant is predicted to causeloss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.Data from control individuals in the 1000 Genomes Project and the NHLBI Exome SequencingProject were not available to assess whether the c.186dupA variant may be a common benign variantin the general population; however, this variant has not been detected previously in the internaldatabase at GeneDx. Therefore, we consider c.186dupA a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs886041799; hg19: chr7-74193459;