rs562308643

chr16-88643546-G-Achr16-88643546-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1 PM2 BP4_Strong BS1_Supporting

The NM_000101.4(CYBA):c.395C>T(p.Thr132Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000043 in 1,534,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T132T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: CYBA NM_000101.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.0780

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 Likely_benign. Variant got -1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000101.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03098157).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000171 (26/152174) while in subpopulation AFR AF= 0.000553 (23/41556). AF 95% confidence interval is 0.000378. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYBA	NM_000101.4	c.395C>T	p.Thr132Met	missense_variant	6/6	ENST00000261623.8
CYBA	XM_011522905.4	c.*1620C>T		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYBA	ENST00000261623.8	c.395C>T	p.Thr132Met	missense_variant	6/6	1	NM_000101.4	P1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152066 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000456 AC: 6 AN: 131492 Hom.: 0 AF XY: 0.0000277 AC XY: 2 AN XY: 72140

Gnomad AFR exome AF: 0.000311

Gnomad AMR exome AF: 0.0000409

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: 0.0000614

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000289 AC: 40 AN: 1382488 Hom.: 0 Cov.: 37 AF XY: 0.0000322 AC XY: 22 AN XY: 682578

Gnomad4 AFR exome AF: 0.000539

Gnomad4 AMR exome AF: 0.0000840

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000167

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000288

Gnomad4 NFE exome AF: 0.0000111

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152174 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74382

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000144 Hom.: 0

Bravo AF: 0.000147

ExAC AF: 0.0000364 AC: 3

Asia WGS AF: 0.000290 AC: 1 AN: 3466

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2023

The c.395C>T (p.T132M) alteration is located in exon 6 (coding exon 6) of the CYBA gene. This alteration results from a C to T substitution at nucleotide position 395, causing the threonine (T) at amino acid position 132 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Chronic granulomatous disease Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 28, 2019

- -

Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 07, 2022

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 132 of the CYBA protein (p.Thr132Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CYBA-related conditions. ClinVar contains an entry for this variant (Variation ID: 567401). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	16
Dann	Benign	0.91
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.22
Sift	Benign	0.11	T
Sift4G	Benign	0.099	T
Polyphen		0.065	B
Vest4		0.089
MutPred		0.29		Gain of catalytic residue at T132 (P = 0.024);
MVP		0.62
MPC		0.18
ClinPred		0.0097	T
GERP RS		-5.6
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.020
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs562308643; hg19: chr16-88709954;