Genetic Variant CYBB:p.Thr307Ala (chrX-37803898-A-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_000397.4(CYBB):c.919A>G(p.Thr307Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000912 in 1,096,928 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 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. T307P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

CYBB
NM_000397.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.86

Publications

5 publications found

Variant links:

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)

CYBB links:

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000397.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYBB	NM_000397.4 link	c.919A>G	p.Thr307Ala	missense_variant	Exon 9 of 13	ENST00000378588.5	NP_000388.2	P04839A0A0S2Z3S6
CYBB	XM_047441855.1 link	c.613A>G	p.Thr205Ala	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 link	c.919A>G	p.Thr307Ala	missense_variant	Exon 9 of 13	1	NM_000397.4	ENSP00000367851.4		P04839
ENSG00000250349	ENST00000465127.1 link	c.171+377898A>G		intron_variant	Intron 3 of 8	5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000549

AC:

AN:

182180

AF XY:

0.0000149

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000367

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.12e-7

AC:

AN:

1096928

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362564

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26358

American (AMR)

AF:

0.0000285

AC:

AN:

35108

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19367

East Asian (EAS)

AF:

0.00

AC:

AN:

30191

South Asian (SAS)

AF:

0.00

AC:

AN:

54099

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40508

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4127

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841142

Other (OTH)

AF:

0.00

AC:

AN:

46028

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.84

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.83

MetaSVM

Uncertain

0.55

MutationAssessor

Benign

0.94

PhyloP100

3.9

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.98

REVEL

Uncertain

0.59

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0090

Polyphen

0.97

Vest4

0.54

MutPred

0.49

Gain of MoRF binding (P = 0.1319);

MVP

0.97

MPC

0.78

ClinPred

0.45

GERP RS

5.7

Varity_R

0.52

gMVP

0.95

Mutation Taster

=13/87

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over