X-37803886-C-T

Variant names:

• chrX-37803886-C-T
• rs137854595
• NM_000397.4:c.907C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3 PP5_Moderate

The NM_000397.4(CYBB):​c.907C>T​(p.His303Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H303N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: CYBB NM_000397.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.74
• Publications: 9 publications found

Genes affected

CYBB (HGNC:2578): (cytochrome b-245 beta chain) Cytochrome b (-245) is composed of cytochrome b alpha (CYBA) and beta (CYBB) chain. It has been proposed as a primary component of the microbicidal oxidase system of phagocytes. CYBB deficiency is one of five described biochemical defects associated with chronic granulomatous disease (CGD). In this disorder, there is decreased activity of phagocyte NADPH oxidase; neutrophils are able to phagocytize bacteria but cannot kill them in the phagocytic vacuoles. The cause of the killing defect is an inability to increase the cell's respiration and consequent failure to deliver activated oxygen into the phagocytic vacuole. [provided by RefSeq, Jul 2008]

CYBB Gene-Disease associations (from GenCC):

• granulomatous disease, chronic, X-linked

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• chronic granulomatous disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency

  Inheritance: XL, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000397.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-37803886-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 10936.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829
• PP5: Variant X-37803886-C-T is Pathogenic according to our data. Variant chrX-37803886-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 265092.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYBB	NM_000397.4	c.907C>T	p.His303Tyr	missense_variant	Exon 9 of 13	ENST00000378588.5	NP_000388.2
CYBB	XM_047441855.1	c.601C>T	p.His201Tyr	missense_variant	Exon 8 of 12		XP_047297811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYBB	ENST00000378588.5	c.907C>T	p.His303Tyr	missense_variant	Exon 9 of 13	1	NM_000397.4	ENSP00000367851.4
ENSG00000250349	ENST00000465127.1	c.171+377886C>T		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Mar 21, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The H303Y missense variant in the CYBB gene has been reported previously in association with X-linked Chronic Granulomatous Disease (Isman-Nelkenbaum et al., 2011; Wolach et al., 2011; Roos et al., 2010). H303Y was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This non-conservative amino acid substitution occurs at a highly conserved position in the FAD-binding FR-type domain; variants in this domain are known to affect the production of residual oxygen intermediates (Kuhns et al., 2010). A missense variant in the same residue, H303N, has been shown to inhibit oxidase activity and abolish NADPH oxidase assembly (Bionda et al., 2004), supporting the functional importance of this region of the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Benign	1.9	L
PhyloP100		5.7
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.83
Sift	Benign	0.036	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.66
MutPred		0.65		Gain of ubiquitination at K299 (P = 0.0913);
MVP		0.94
MPC		1.4
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.86
gMVP		0.98
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs137854595; hg19: chrX-37663139; COSMIC: COSV106544592;