X-37793793-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000397.4(CYBB):​c.466G>T​(p.Ala156Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000914 in 1,094,486 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: CYBB NM_000397.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYBB	NM_000397.4	c.466G>T	p.Ala156Ser	missense_variant	Exon 5 of 13	ENST00000378588.5	NP_000388.2
CYBB	XM_047441855.1	c.160G>T	p.Ala54Ser	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>T	p.Ala156Ser	missense_variant	Exon 5 of 13	1	NM_000397.4	ENSP00000367851.4
ENSG00000250349	ENST00000465127.1	c.171+367793G>T		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 9.14e-7 AC: 1 AN: 1094486 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 360828

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.36	T
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.56	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.7	L
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.49	N
REVEL	Uncertain	0.36
Sift	Benign	0.26	T
Sift4G	Benign	0.25	T
Polyphen		0.12	B
Vest4		0.22
MutPred		0.64		Loss of helix (P = 0.0196);
MVP		0.90
MPC		0.56
ClinPred		0.38	T
GERP RS		5.7
Varity_R		0.26
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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-37653046;