Genetic Variant CYBA:p.Ala125Thr (chr16-88643568-C-T) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000101.4(CYBA):c.373G>A(p.Ala125Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000145 in 1,380,492 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 Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. A125A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CYBA
NM_000101.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.29

Publications

10 publications found

Variant links:

Genes affected

CYBA (HGNC:2577): (cytochrome b-245 alpha chain) Cytochrome b is comprised of a light chain (alpha) and a heavy chain (beta). This gene encodes the light, alpha subunit which has been proposed as a primary component of the microbicidal oxidase system of phagocytes. Mutations in this gene are associated with autosomal recessive chronic granulomatous disease (CGD), that is characterized by the failure of activated phagocytes to generate superoxide, which is important for the microbicidal activity of these cells. [provided by RefSeq, Jul 2008]

CYBA Gene-Disease associations (from GenCC):

granulomatous disease, chronic, autosomal recessive, cytochrome b-negative
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
chronic granulomatous disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CYBA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000101.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.996

PP5

Variant 16-88643568-C-T is Pathogenic according to our data. Variant chr16-88643568-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2267.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYBA	NM_000101.4 link	c.373G>A	p.Ala125Thr	missense_variant	Exon 6 of 6	ENST00000261623.8	NP_000092.2	P13498B4DT46
CYBA	XM_011522905.4 link	c.*1598G>A		3_prime_UTR_variant	Exon 6 of 6		XP_011521207.1	H3BNP7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYBA	ENST00000261623.8 link	c.373G>A	p.Ala125Thr	missense_variant	Exon 6 of 6	1	NM_000101.4	ENSP00000261623.3		P13498

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1380492

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

681462

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31468

American (AMR)

AF:

0.00

AC:

AN:

35618

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25070

East Asian (EAS)

AF:

0.00

AC:

AN:

35686

South Asian (SAS)

AF:

0.00

AC:

AN:

79104

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34312

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4062

European-Non Finnish (NFE)

AF:

0.00000186

AC:

AN:

1077582

Other (OTH)

AF:

0.00

AC:

AN:

57590

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative

Pathogenic:1

Jun 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Uncertain

(source)

DANN

Benign

0.85

DEOGEN2

Pathogenic

0.96

Eigen

Uncertain

0.40

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

1.0

MetaSVM

Pathogenic

0.90

MutationAssessor

Uncertain

2.7

PhyloP100

5.3

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.5

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.93

MutPred

0.94

Loss of stability (P = 0.0201);

MVP

0.97

MPC

0.69

ClinPred

0.87

GERP RS

4.2

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.7

Varity_R

0.51

gMVP

0.81

Mutation Taster

=53/47

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over