chr7-74779296-G-A

Position:

• chr7-74779296-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000265.7(NCF1):​c.269G>A​(p.Arg90His) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R90C) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 23)
  • Exomes 𝑓: 0.00015 (100 hom.)
  • Failed GnomAD Quality Control
• Consequence: NCF1 NM_000265.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:4
• Conservation: PhyloP100: 7.27

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.066622585).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCF1	NM_000265.7	c.269G>A	p.Arg90His	missense_variant	4/11	ENST00000289473.11	NP_000256.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCF1	ENST00000289473.11	c.269G>A	p.Arg90His	missense_variant	4/11	1	NM_000265.7	ENSP00000289473.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 66 AN: 145122 Hom.: 0 Cov.: 23 FAILED QC

Gnomad AFR AF: 0.00107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000275

Gnomad ASJ AF: 0.000293

Gnomad EAS AF: 0.000425

Gnomad SAS AF: 0.00113

Gnomad FIN AF: 0.0000987

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000121

Gnomad OTH AF: 0.00203

GnomAD3 exomes AF: 0.00110 AC: 268 AN: 244730 Hom.: 63 AF XY: 0.00107 AC XY: 143 AN XY: 133024

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.000349

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.00585

Gnomad SAS exome AF: 0.000563

Gnomad FIN exome AF: 0.00342

Gnomad NFE exome AF: 0.000362

Gnomad OTH exome AF: 0.000667

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000152 AC: 221 AN: 1456782 Hom.: 100 Cov.: 31 AF XY: 0.000221 AC XY: 160 AN XY: 724466

Gnomad4 AFR exome AF: 0.000271

Gnomad4 AMR exome AF: 0.000135

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00110

Gnomad4 SAS exome AF: 0.00154

Gnomad4 FIN exome AF: 0.000151

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000454 AC: 66 AN: 145244 Hom.: 0 Cov.: 23 AF XY: 0.000538 AC XY: 38 AN XY: 70664

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.000275

Gnomad4 ASJ AF: 0.000293

Gnomad4 EAS AF: 0.000426

Gnomad4 SAS AF: 0.00113

Gnomad4 FIN AF: 0.0000987

Gnomad4 NFE AF: 0.000121

Gnomad4 OTH AF: 0.00201

Alfa AF: 0.0250 Hom.: 8

ExAC AF: 0.00140 AC: 170

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Granulomatous disease, chronic, X-linked Pathogenic:1

Likely 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

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 26, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.067	T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Pathogenic	3.3	M
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.79	P
Vest4		0.67
MVP		0.92
ClinPred		0.11	T
GERP RS		3.4
Varity_R		0.65
gMVP		0.81

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: rs201802880; hg19: chr7-74193642; COSMIC: COSV56876334; COSMIC: COSV56876334;