rs145360423

chr7-74783529-G-A

Variant summary

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

The NM_000265.7(NCF1):c.579G>A(p.Trp193Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000552 in 152,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00037 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NCF1 NM_000265.7 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 8.98

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 7-74783529-G-A is Pathogenic according to our data. Variant chr7-74783529-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 426990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-74783529-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCF1	NM_000265.7	c.579G>A	p.Trp193Ter	stop_gained	7/11	ENST00000289473.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCF1	ENST00000289473.11	c.579G>A	p.Trp193Ter	stop_gained	7/11	1	NM_000265.7	P1

Frequencies

GnomAD3 genomes AF: 0.000553 AC: 84 AN: 151994 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000688 AC: 172 AN: 250032 Hom.: 0 AF XY: 0.000739 AC XY: 100 AN XY: 135390

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.0115

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000301

Gnomad OTH exome AF: 0.00196

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000369 AC: 539 AN: 1459478 Hom.: 0 Cov.: 32 AF XY: 0.000391 AC XY: 284 AN XY: 726024

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.0106

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000813

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000151

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152112 Hom.: 0 Cov.: 28 AF XY: 0.000471 AC XY: 35 AN XY: 74366

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000394

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.00224 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000601 AC: 73

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 1 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The stop gained variant c.579G>A (p.Trp193Ter) in NCF1 gene has previously been reported in homozygous state in multiple patients affected with chronic granulomatous disease (Al-Zadjali et al. 2015). The variant is novel (not in any individuals) in 1000 Genomes and is present in the gnomAD exomes database with a frequency of 0.07%. This variant has been reported to the ClinVar database as Pathogenic. This variant results in a premature termination codon which is predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease. The nucleotide change in NCF1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 28, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.064%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. A pathogenic variant is reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000426990 / PMID: 11920901). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Feb 05, 2020	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Oct 23, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2022	Nonsense 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; This variant is associated with the following publications: (PMID: 18708296, 31172494, 16972229, 26460255, 25525159, 11920901, 27220316, 27701760, 28886419, 29947158, 29454792, 29331982, 24446915, 30963593, 30487145, 29411231, 31980526, 32736065, 33629196, 34573280, 31589614, 33746979, 35464432, 35112591) -

Chronic granulomatous disease due to deficiency of NCF-1 Pathogenic:1

Pathogenic, no assertion criteria provided

curation

Reproductive Health Research and Development, BGI Genomics

Jan 06, 2020

NM_000265.4:c.579G>A in the NCF1 gene has an allele frequency of 0.011 in Ashkenazi Jewish subpopulation in the gnomAD database. The NCF1 c.579G>A (p.Trp193*) variant results in a premature termination codon, predicted to cause a truncated or absent protein due to nonsense mediated decay. This variant has been detected in 13 patients affected with chronic granulomatous disease, all in homozygous states (PMID: 24446915). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PVS1; PM3; PP4. -

Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 Pathogenic:1

Pathogenic, no assertion criteria provided

curation

Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University

Dec 30, 2017

- -

Chronic granulomatous disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 09, 2022

Variant summary: NCF1 c.579G>A (p.Trp193X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar. The variant allele was found at a frequency of 0.00069 in 250032 control chromosomes (gnomAD). This frequency is not higher than predicted for a pathogenic variant in NCF1 causing Chronic Granulomatous Disease (0.00069 vs 0.0011). c.579G>A has been reported in the literature in multiple individuals affected with Chronic Granulomatous Disease and the variant segregated with disease. These data indicate that the variant is very likely to be associated with disease. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	37
Dann	Uncertain	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	A
Vest4		0.84
GERP RS		4.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs145360423; hg19: chr7-74197872;