rs137853324

Positions:

• chrX-154564372-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PP5_Moderate

The NM_001099857.5(IKBKG):​c.1171G>T​(p.Glu391Ter) variant causes a stop gained change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: IKBKG NM_001099857.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.04

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0706 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PP5: Variant X-154564372-G-T is Pathogenic according to our data. Variant chrX-154564372-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 11453.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IKBKG	NM_001099857.5	c.1171G>T	p.Glu391Ter	stop_gained	10/10	ENST00000594239.6	NP_001093327.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IKBKG	ENST00000594239.6	c.1171G>T	p.Glu391Ter	stop_gained	10/10	1	NM_001099857.5	ENSP00000471166	P3

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 30, 2019

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 28 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 15661019, 18851874, 26230867, 18350553, 19375390, 21309033, 11047757, 26802121, 26740240) -

Ectodermal dysplasia and immunodeficiency 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A
Vest4		0.64
GERP RS		3.2

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: rs137853324; hg19: chrX-153792587;