Variant X-37803898-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3

The NM_000397.4(CYBB):c.919A>G(p.Thr307Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000912 in 1,096,928 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T307P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

CYBB
NM_000397.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.86

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:

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 287) in uniprot entity CY24B_HUMAN there are 20 pathogenic changes around while only 0 benign (100%) in NM_000397.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYBB	NM_000397.4 linkuse as main transcript	c.919A>G	p.Thr307Ala	missense_variant	9/13	ENST00000378588.5	NP_000388.2	P04839A0A0S2Z3S6
CYBB	XM_047441855.1 linkuse as main transcript	c.613A>G	p.Thr205Ala	missense_variant	8/12		XP_047297811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYBB	ENST00000378588.5 linkuse as main transcript	c.919A>G	p.Thr307Ala	missense_variant	9/13	1	NM_000397.4	ENSP00000367851.4		P04839
ENSG00000250349	ENST00000465127.1 linkuse as main transcript	c.171+377898A>G		intron_variant		5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000549

AC:

AN:

182180

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

67022

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000367

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:

9.12e-7

AC:

AN:

1096928

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362564

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000285

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.84

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.83

MetaSVM

Uncertain

0.55

MutationAssessor

Benign

0.94

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.98

REVEL

Uncertain

0.59

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0090

Polyphen

0.97

Vest4

0.54

MutPred

0.49

Gain of MoRF binding (P = 0.1319);

MVP

0.97

MPC

0.78

ClinPred

0.45

GERP RS

5.7

Varity_R

0.52

gMVP

0.95

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over