rs145620748

Positions:

chrX-37805013-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_000397.4(CYBB):c.1159G>A(p.Val387Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000752 in 1,210,124 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 24 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., 11 hem., cov: 24)

Exomes 𝑓: 0.000038 ( 0 hom. 13 hem. )

Consequence

CYBB
NM_000397.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 4.41

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04415235).

BP6

Variant X-37805013-G-A is Benign according to our data. Variant chrX-37805013-G-A is described in ClinVar as [Benign]. Clinvar id is 533559.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-37805013-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000435 (49/112688) while in subpopulation AFR AF= 0.00151 (47/31054). AF 95% confidence interval is 0.00117. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYBB	NM_000397.4 linkuse as main transcript	c.1159G>A	p.Val387Ile	missense_variant	10/13	ENST00000378588.5	NP_000388.2
CYBB	XM_047441855.1 linkuse as main transcript	c.853G>A	p.Val285Ile	missense_variant	9/12		XP_047297811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CYBB	ENST00000378588.5 linkuse as main transcript	c.1159G>A	p.Val387Ile	missense_variant	10/13	1	NM_000397.4	ENSP00000367851	P1
CYBB	ENST00000696171.1 linkuse as main transcript	c.1063G>A	p.Val355Ile	missense_variant	9/12			ENSP00000512462
CYBB	ENST00000696170.1 linkuse as main transcript	c.*668G>A		3_prime_UTR_variant, NMD_transcript_variant	9/12			ENSP00000512461

Frequencies

GnomAD3 genomes

AF:

0.000435

AC:

AN:

112637

Hom.:

Cov.:

AF XY:

0.000316

AC XY:

AN XY:

34801

show subpopulations

Gnomad AFR

AF:

0.00152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000187

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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:

0.000142

AC:

AN:

182708

Hom.:

AF XY:

0.000148

AC XY:

AN XY:

67472

show subpopulations

Gnomad AFR exome

AF:

0.00152

Gnomad AMR exome

AF:

0.000220

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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

AF:

0.0000383

AC:

AN:

1097436

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

363038

show subpopulations

Gnomad4 AFR exome

AF:

0.00129

Gnomad4 AMR exome

AF:

0.000171

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.000435

AC:

AN:

112688

Hom.:

Cov.:

AF XY:

0.000316

AC XY:

AN XY:

34862

show subpopulations

Gnomad4 AFR

AF:

0.00151

Gnomad4 AMR

AF:

0.000187

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0283

Hom.:

2355

Bravo

AF:

0.000548

ESP6500AA

AF:

0.00130

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000239

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Granulomatous disease, chronic, X-linked

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

CYBB-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.044

MetaSVM

Uncertain

0.099

MutationAssessor

Benign

0.34

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.47

REVEL

Uncertain

0.42

Sift

Benign

0.49

Sift4G

Benign

0.48

Polyphen

0.47

Vest4

0.30

MVP

0.81

MPC

0.69

ClinPred

0.043

GERP RS

5.9

Varity_R

0.40

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

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