rs2233419

chr14-35402754-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020529.3(NFKBIA):c.636+17C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,613,940 control chromosomes in the GnomAD database, including 26,631 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1899 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24732 hom.)
• Consequence: NFKBIA NM_020529.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.163

Genes affected

NFKBIA (HGNC:7797): (NFKB inhibitor alpha) This gene encodes a member of the NF-kappa-B inhibitor family, which contain multiple ankrin repeat domains. The encoded protein interacts with REL dimers to inhibit NF-kappa-B/REL complexes which are involved in inflammatory responses. The encoded protein moves between the cytoplasm and the nucleus via a nuclear localization signal and CRM1-mediated nuclear export. Mutations in this gene have been found in ectodermal dysplasia anhidrotic with T-cell immunodeficiency autosomal dominant disease. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 14-35402754-G-A is Benign according to our data. Variant chr14-35402754-G-A is described in ClinVar as [Benign]. Clinvar id is 1166715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFKBIA	NM_020529.3	c.636+17C>T		intron_variant		ENST00000216797.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFKBIA	ENST00000216797.10	c.636+17C>T		intron_variant		1	NM_020529.3	P1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22922 AN: 152060 Hom.: 1899 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.0331

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.190

Gnomad OTH AF: 0.139

GnomAD3 exomes AF: 0.153 AC: 38554 AN: 251316 Hom.: 3223 AF XY: 0.156 AC XY: 21143 AN XY: 135862

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.136

Gnomad ASJ exome AF: 0.0995

Gnomad EAS exome AF: 0.0257

Gnomad SAS exome AF: 0.158

Gnomad FIN exome AF: 0.153

Gnomad NFE exome AF: 0.188

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.180 AC: 263744 AN: 1461762 Hom.: 24732 Cov.: 37 AF XY: 0.179 AC XY: 130388 AN XY: 727190

Gnomad4 AFR exome AF: 0.105

Gnomad4 AMR exome AF: 0.135

Gnomad4 ASJ exome AF: 0.104

Gnomad4 EAS exome AF: 0.0369

Gnomad4 SAS exome AF: 0.161

Gnomad4 FIN exome AF: 0.158

Gnomad4 NFE exome AF: 0.195

Gnomad4 OTH exome AF: 0.168

GnomAD4 genome AF: 0.151 AC: 22940 AN: 152178 Hom.: 1899 Cov.: 32 AF XY: 0.148 AC XY: 10978 AN XY: 74404

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.143

Gnomad4 ASJ AF: 0.103

Gnomad4 EAS AF: 0.0331

Gnomad4 SAS AF: 0.149

Gnomad4 FIN AF: 0.159

Gnomad4 NFE AF: 0.190

Gnomad4 OTH AF: 0.138

Alfa AF: 0.158 Hom.: 626

Bravo AF: 0.147

Asia WGS AF: 0.0990 AC: 347 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 12, 2023

This variant is classified as Benign based on local population frequency. This variant was detected in 26% of patients studied by a panel of primary immunodeficiencies. Number of patients: 25. Only high quality variants are reported. -

Ectodermal dysplasia and immunodeficiency 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	5.4
Dann	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs2233419; hg19: chr14-35871960; COSMIC: COSV53751722; COSMIC: COSV53751722;