rs8053867

Positions:

• chr16-88650978-T-A
• chr16-88650978-T-C
• chr16-88650978-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000101.4(CYBA):​c.36A>T​(p.Glu12Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E12K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYBA NM_000101.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.114

Genes affected

CYBA (HGNC:2577): (cytochrome b-245 alpha chain) Cytochrome b is comprised of a light chain (alpha) and a heavy chain (beta). This gene encodes the light, alpha subunit which has been proposed as a primary component of the microbicidal oxidase system of phagocytes. Mutations in this gene are associated with autosomal recessive chronic granulomatous disease (CGD), that is characterized by the failure of activated phagocytes to generate superoxide, which is important for the microbicidal activity of these cells. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYBA	NM_000101.4	c.36A>T	p.Glu12Asp	missense_variant	1/6	ENST00000261623.8
CYBA	XM_011522905.4	c.36A>T	p.Glu12Asp	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYBA	ENST00000261623.8	c.36A>T	p.Glu12Asp	missense_variant	1/6	1	NM_000101.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.93e-7 AC: 1 AN: 1443910 Hom.: 0 Cov.: 60 AF XY: 0.00 AC XY: 0 AN XY: 716940

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: 0.0000201

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;D;.;D
Eigen	Benign	-0.012
Eigen_PC	Benign	-0.050
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.6	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Pathogenic	0.65
Sift	Benign	0.040	D;D;T;D
Sift4G	Uncertain	0.020	D;D;D;.
Polyphen		0.87	P;.;.;.
Vest4		0.57
MutPred		0.88		Gain of catalytic residue at E12 (P = 0.3664);Gain of catalytic residue at E12 (P = 0.3664);Gain of catalytic residue at E12 (P = 0.3664);Gain of catalytic residue at E12 (P = 0.3664);
MVP		0.86
MPC		0.63
ClinPred		0.91	D
GERP RS		2.3
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.24
gMVP		0.90

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: rs8053867; hg19: chr16-88717386;