rs137854590

Variant names:

• chrX-37793793-G-A
• rs137854590
• NM_000397.4:c.466G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-37793793-G-A
• chrX-37793793-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3 PP5_Moderate

The NM_000397.4(CYBB):​c.466G>A​(p.Ala156Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000914 in 1,094,487 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. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: CYBB NM_000397.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 4.39

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]

ENSG00000250349 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain Ferric oxidoreductase (size 232) in uniprot entity CY24B_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) in NM_000397.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813
• PP5: Variant X-37793793-G-A is Pathogenic according to our data. Variant chrX-37793793-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10925.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-37793793-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYBB	NM_000397.4	c.466G>A	p.Ala156Thr	missense_variant	Exon 5 of 13	ENST00000378588.5	NP_000388.2
CYBB	XM_047441855.1	c.160G>A	p.Ala54Thr	missense_variant	Exon 4 of 12		XP_047297811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYBB	ENST00000378588.5	c.466G>A	p.Ala156Thr	missense_variant	Exon 5 of 13	1	NM_000397.4	ENSP00000367851.4
ENSG00000250349	ENST00000465127.1	c.171+367793G>A		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 9.14e-7 AC: 1 AN: 1094487 Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 1 AN XY: 360829

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Granulomatous disease, chronic, X-linked, variant Pathogenic:1

Jun 01, 1991

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Granulomatous disease, chronic, X-linked Pathogenic:1

Dec 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 156 of the CYBB protein (p.Ala156Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with chronic granulomatous disease (PMID: 1710153, 20729109, 29560547). ClinVar contains an entry for this variant (Variation ID: 10925). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CYBB protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects CYBB function (PMID: 25252997). For these reasons, this variant has been classified as Pathogenic. -

not provided Other:1

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.72	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.15	N
REVEL	Uncertain	0.50
Sift	Benign	0.25	T
Sift4G	Benign	0.26	T
Polyphen		0.064	B
Vest4		0.25
MutPred		0.81		Loss of helix (P = 0.0196);
MVP		1.0
MPC		0.63
ClinPred		0.36	T
GERP RS		5.7
Varity_R		0.25
gMVP		0.83

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

LitVar

Other links and lift over

dbSNP: rs137854590; hg19: chrX-37653046;