X-154542390-G-A

Variant names:

• chrX-154542390-G-A
• rs782367664
• ENST00000618670.4:c.127G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM1 BP4_Moderate BS2_Supporting

The NM_001099856.6(IKBKG):​c.127G>A​(p.Gly43Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000166 in 1,205,362 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G43A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.000016 (0 hom. 3 hem.)
• Consequence: IKBKG NM_001099856.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.759

Genes affected

IKBKG (HGNC:5961): (inhibitor of nuclear factor kappa B kinase regulatory subunit gamma) This gene encodes the regulatory subunit of the inhibitor of kappaB kinase (IKK) complex, which activates NF-kappaB resulting in activation of genes involved in inflammation, immunity, cell survival, and other pathways. Mutations in this gene result in incontinentia pigmenti, hypohidrotic ectodermal dysplasia, and several other types of immunodeficiencies. A pseudogene highly similar to this locus is located in an adjacent region of the X chromosome. [provided by RefSeq, Mar 2016]

G6PD (HGNC:4057): (glucose-6-phosphate dehydrogenase) This gene encodes glucose-6-phosphate dehydrogenase. This protein is a cytosolic enzyme encoded by a housekeeping X-linked gene whose main function is to produce NADPH, a key electron donor in the defense against oxidizing agents and in reductive biosynthetic reactions. G6PD is remarkable for its genetic diversity. Many variants of G6PD, mostly produced from missense mutations, have been described with wide ranging levels of enzyme activity and associated clinical symptoms. G6PD deficiency may cause neonatal jaundice, acute hemolysis, or severe chronic non-spherocytic hemolytic anemia. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM1: In a modified_residue Phosphoserine; by IKKB (size 0) in uniprot entity NEMO_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.07725933).
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PD	NM_001360016.2	c.120+3646C>T		intron_variant	Intron 2 of 12	ENST00000393562.10	NP_001346945.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10	c.120+3646C>T		intron_variant	Intron 2 of 12	1	NM_001360016.2	ENSP00000377192.3

Frequencies

GnomAD3 genomes AF: 0.0000267 AC: 3 AN: 112386 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000188

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000813 AC: 14 AN: 172108 AF XY: 0.0000506

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000544

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000156 AC: 17 AN: 1092976 Hom.: 0 Cov.: 30 AF XY: 0.00000836 AC XY: 3 AN XY: 358896

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 26161

Gnomad4 AMR exome AF: 0.000491 AC: 17 AN: 34595

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 19232

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 29779

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 53115

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 40471

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 839603

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 45898

GnomAD4 genome AF: 0.0000267 AC: 3 AN: 112386 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34546

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.000188 AC: 0.000188041 AN: 0.000188041

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000188 AC: 0.0000187829 AN: 0.0000187829

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Incontinentia pigmenti syndrome;C1846008:Ectodermal dysplasia and immunodeficiency 1;C1970879:Immunodeficiency 33;C5676885:Autoinflammatory disease, X-linked Uncertain:1

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IKBKG NM_001099856.2 exon 1 p.Gly43Arg (c.127G>A): This variant has not been reported in the literature but is present in 14/25632 Latino alleles including 2 hemizygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs782367664). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Incontinentia pigmenti syndrome;C1846008:Ectodermal dysplasia and immunodeficiency 1;C1970879:Immunodeficiency 33;C4303737:Anhidrotic ectodermal dysplasia-immunodeficiency-osteopetrosis-lymphedema syndrome Uncertain:1

Jul 03, 2018

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IKBKG NM_001099856.2 exon 1 p.Gly43Arg (c.127G>A): This variant has not been reported in the literature but is present in 14/25632 Latino alleles including 2 hemizygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs782367664). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	4.3
DANN	Benign	0.94
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-0.31	T
PrimateAI	Benign	0.32	T
Polyphen		0.63	P
Vest4		0.25
MutPred		0.14		Gain of MoRF binding (P = 0.045);
MVP		0.43
ClinPred		0.037	T
GERP RS		1.5
gMVP		0.030
Mutation Taster		=100/0	polymorphism

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: rs782367664; hg19: chrX-153770605;