X-37780120-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM1BP4_StrongBP6_ModerateBS2

The NM_000397.4(CYBB):c.43A>G(p.Ile15Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000179 in 111,710 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I15F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 9.2e-7 ( 0 hom. 1 hem. )

Failed GnomAD Quality Control

Consequence

CYBB
NM_000397.4 missense, splice_region

Scores

Splicing: ADA: 0.0001208

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 1.93

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_000397.4

BP4

Computational evidence support a benign effect (MetaRNN=0.056973934).

BP6

Variant X-37780120-A-G is Benign according to our data. Variant chrX-37780120-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1149798.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYBB	NM_000397.4 linkuse as main transcript	c.43A>G	p.Ile15Val	missense_variant, splice_region_variant	1/13	ENST00000378588.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYBB	ENST00000378588.5 linkuse as main transcript	c.43A>G	p.Ile15Val	missense_variant, splice_region_variant	1/13	1	NM_000397.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111657

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33841

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000562

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

182921

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

67469

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000145

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

9.19e-7

AC:

AN:

1088062

Hom.:

Cov.:

AF XY:

0.00000283

AC XY:

AN XY:

353766

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000332

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111710

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33904

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000564

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Granulomatous disease, chronic, X-linked

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 01, 2023

- -

Chronic granulomatous disease

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.26

Cadd

Benign

9.6

Dann

Benign

0.87

DEOGEN2

Benign

0.21

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.67

M_CAP

Uncertain

0.098

MetaRNN

Benign

0.057

MetaSVM

Benign

-0.49

MutationAssessor

Benign

0.64

MutationTaster

Benign

0.87

D;D;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.39

REVEL

Uncertain

0.29

Sift

Benign

0.49

Sift4G

Benign

0.57

Polyphen

0.0

Vest4

0.074

MutPred

0.34

Gain of glycosylation at S11 (P = 0.2071);

MVP

0.55

MPC

0.50

ClinPred

0.011

GERP RS

0.24

Varity_R

0.059

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00012

dbscSNV1_RF

Benign

0.014

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over