rs8904

chr14-35402011-G-Achr14-35402011-G-Cchr14-35402011-G-T

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.*2C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,611,958 control chromosomes in the GnomAD database, including 121,408 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15318 hom., cov: 31)
  • Exomes 𝑓: 0.38 (106090 hom.)
• Consequence: NFKBIA NM_020529.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.295

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=-0.78).
• BP6: Variant 14-35402011-G-A is Benign according to our data. Variant chr14-35402011-G-A is described in ClinVar as [Benign]. Clinvar id is 313108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-35402011-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFKBIA	NM_020529.3	c.*2C>T		3_prime_UTR_variant	6/6	ENST00000216797.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFKBIA	ENST00000216797.10	c.*2C>T		3_prime_UTR_variant	6/6	1	NM_020529.3	P1

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66218 AN: 151384 Hom.: 15298 Cov.: 31

Gnomad AFR AF: 0.595

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.398

Gnomad EAS AF: 0.398

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.402

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.425

GnomAD3 exomes AF: 0.393 AC: 98581 AN: 251136 Hom.: 19908 AF XY: 0.395 AC XY: 53624 AN XY: 135812

Gnomad AFR exome AF: 0.596

Gnomad AMR exome AF: 0.286

Gnomad ASJ exome AF: 0.418

Gnomad EAS exome AF: 0.421

Gnomad SAS exome AF: 0.418

Gnomad FIN exome AF: 0.401

Gnomad NFE exome AF: 0.381

Gnomad OTH exome AF: 0.376

GnomAD4 exome AF: 0.377 AC: 550843 AN: 1460456 Hom.: 106090 Cov.: 37 AF XY: 0.378 AC XY: 274984 AN XY: 726578

Gnomad4 AFR exome AF: 0.608

Gnomad4 AMR exome AF: 0.293

Gnomad4 ASJ exome AF: 0.422

Gnomad4 EAS exome AF: 0.359

Gnomad4 SAS exome AF: 0.411

Gnomad4 FIN exome AF: 0.396

Gnomad4 NFE exome AF: 0.369

Gnomad4 OTH exome AF: 0.391

GnomAD4 genome AF: 0.437 AC: 66282 AN: 151502 Hom.: 15318 Cov.: 31 AF XY: 0.435 AC XY: 32217 AN XY: 74008

Gnomad4 AFR AF: 0.595

Gnomad4 AMR AF: 0.336

Gnomad4 ASJ AF: 0.398

Gnomad4 EAS AF: 0.397

Gnomad4 SAS AF: 0.433

Gnomad4 FIN AF: 0.402

Gnomad4 NFE AF: 0.379

Gnomad4 OTH AF: 0.432

Alfa AF: 0.390 Hom.: 23172

Bravo AF: 0.435

Asia WGS AF: 0.418 AC: 1453 AN: 3478

EpiCase AF: 0.392

EpiControl AF: 0.386

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
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 56% of patients studied by a panel of primary immunodeficiencies. Number of patients: 54. Only high quality variants are reported. -

Ectodermal dysplasia and immunodeficiency 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.27
Dann	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs8904; hg19: chr14-35871217; COSMIC: COSV53754079; COSMIC: COSV53754079;