rs119103269

Variant names:

• chr16-88643568-C-T
• rs119103269
• NM_000101.4:c.373G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-88643568-C-T
• chr16-88643568-C-A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000101.4(CYBA):​c.373G>A​(p.Ala125Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000145 in 1,380,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. A125A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CYBA NM_000101.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.29
• Publications: 10 publications found

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]

CYBA Gene-Disease associations (from GenCC):

• granulomatous disease, chronic, autosomal recessive, cytochrome b-negative

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• chronic granulomatous disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000101.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 16-88643568-C-T is Pathogenic according to our data. Variant chr16-88643568-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2267.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000101.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYBA	NM_000101.4	MANE Select	c.373G>A	p.Ala125Thr	missense	Exon 6 of 6	NP_000092.2	P13498

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYBA	ENST00000261623.8	TSL:1 MANE Select	c.373G>A	p.Ala125Thr	missense	Exon 6 of 6	ENSP00000261623.3	P13498
	CYBA	ENST00000696161.1		c.503G>A	p.Gly168Asp	missense	Exon 6 of 6	ENSP00000512451.1	A0A8Q3WL26
	CYBA	ENST00000967613.1		c.421G>A	p.Ala141Thr	missense	Exon 7 of 7	ENSP00000637672.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1380492 Hom.: 0 Cov.: 37 AF XY: 0.00000147 AC XY: 1 AN XY: 681462

African (AFR) AF: 0.00 AC: 0 AN: 31468

American (AMR) AF: 0.00 AC: 0 AN: 35618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25070

East Asian (EAS) AF: 0.00 AC: 0 AN: 35686

South Asian (SAS) AF: 0.00 AC: 0 AN: 79104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4062

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1077582

Other (OTH) AF: 0.00 AC: 0 AN: 57590

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	26
DANN	Benign	0.85
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.40
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.94		Loss of stability (P = 0.0201)
MVP		0.97
MPC		0.69
ClinPred		0.87	D
GERP RS		4.2
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.51
gMVP		0.81
Mutation Taster		=53/47	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs119103269; hg19: chr16-88709976;