rs4029402

Positions:

• chr7-74777266-GGT-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000265.7(NCF1):​c.75_76delGT​(p.Tyr26fs) variant causes a frameshift, splice region change. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 22)
  • Exomes 𝑓: 0.000088 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NCF1 NM_000265.7 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.07

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 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 21 pathogenic variants in the truncated region.
• PP5: Variant 7-74777266-GGT-G is Pathogenic according to our data. Variant chr7-74777266-GGT-G is described in ClinVar as [Pathogenic]. Clinvar id is 2249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-74777266-GGT-G is described in Lovd as [Pathogenic]. Variant chr7-74777266-GGT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCF1	NM_000265.7	c.75_76delGT	p.Tyr26fs	frameshift_variant, splice_region_variant	2/11	ENST00000289473.11	NP_000256.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCF1	ENST00000289473.11	c.75_76delGT	p.Tyr26fs	frameshift_variant, splice_region_variant	2/11	1	NM_000265.7	ENSP00000289473.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 124 AN: 145162 Hom.: 0 Cov.: 22 FAILED QC

Gnomad AFR AF: 0.000984

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.000926

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00192

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.000502

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000881 AC: 128 AN: 1453404 Hom.: 0 AF XY: 0.0000802 AC XY: 58 AN XY: 723180

Gnomad4 AFR exome AF: 0.000181

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.000195

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000151

Gnomad4 NFE exome AF: 0.0000859

Gnomad4 OTH exome AF: 0.000201

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000854 AC: 124 AN: 145266 Hom.: 0 Cov.: 22 AF XY: 0.00111 AC XY: 79 AN XY: 70958

Gnomad4 AFR AF: 0.000981

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.000926

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00192

Gnomad4 NFE AF: 0.000663

Gnomad4 OTH AF: 0.000496

Alfa AF: 0.0153 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 1 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Apr 22, 2022	This sequence change is a deletion of 2 bp in exon 2 (of 11) of NCF1 that is predicted to create a premature termination codon at position 51, p.(Tyr26Hisfs*26). It is expected to result in nonsense-mediated decay, and loss of function is an established mechanism of disease for this gene (PVS1; ClinVar). The variant does not pass quality control in the gnomAD dataset, and thus cannot be assessed for population frequency (gnomAD v2.1, v3.0). Homozygosity of this variant is the most common cause of chronic granulomatous disease (CGD) due to deficiency of NCF1, produced by a recombination event between NCF1 & pseudogenes (PMID: 9329953). It has been identified in the homozygous and to a lesser degree compound heterozygous state with a second pathogenic allele in multiple CGD cases, and segregation with disease has been reported in over 12 families (PM3_VeryStrong, PP1_Strong; examples in PMID: 11133775, 16972229, 21190454). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_VeryStrong, PP1_Strong. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 13, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Dec 18, 2024	- -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Aug 09, 2012	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	NCF1: PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2020	Is the most common cause of autosomal recessive chronic granulomatous disease (CGD); has a carrier frequency of 1:250 in the population (Leiding et al., 2012); Accounts for more than 95% of pathogenic variants in the NCF1 gene (Noack et al., 2001); Arises from a recurrent gene conversion event between NCF1 and flanking pseudogenes containing the dinucleotide deletion (Leiding et al., 2012); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; No reliable data available from control populations to assess the frequency of this variant as the variant is pseudogene-derived; This variant is associated with the following publications: (PMID: 22138397, 22876374, 10706888, 2011585, 26409780, 27699571, 27699569, 27701760, 28130637, 29560547, 11133775, 8147881, 30651282, 30470980, 30409207, 30319683, 31631731, 31482473, 31813112, 32040803, 33365035) -

Granulomatous disease, chronic, X-linked Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"

May 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: 3
DS_AL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4029402; hg19: chr7-74191612;