NCF1 p.Gly192Cys

Variant names:

• chr7-74783061-G-T
• NM_000265.7:c.574G>T
• NCF1 p.Gly192Cys

Your query was ambiguous. Multiple possible variants found:

• chr7-74783061-G-T
• chr7-74783061-GGT-TGC

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_000265.7(NCF1):​c.574G>T​(p.Gly192Cys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G192S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 29)
• Consequence: NCF1 NM_000265.7 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.25
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• chronic granulomatous disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-74783061-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2255.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000265.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCF1	NM_000265.7	MANE Select	c.574G>T	p.Gly192Cys	missense splice_region	Exon 6 of 11	NP_000256.4	P14598-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCF1	ENST00000289473.11	TSL:1 MANE Select	c.574G>T	p.Gly192Cys	missense splice_region	Exon 6 of 11	ENSP00000289473.4	P14598-1
	NCF1	ENST00000969823.1		c.574G>T	p.Gly192Cys	missense splice_region	Exon 6 of 12	ENSP00000639882.1
	NCF1	ENST00000969822.1		c.574G>T	p.Gly192Cys	missense splice_region	Exon 6 of 11	ENSP00000639881.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		9.3
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Varity_R		0.96
gMVP		0.78
Mutation Taster		=16/84	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: -22
DS_DL_spliceai		0.61		Position offset: 0

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr7-74197404;