14-35401887-C-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.*126G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,053,372 control chromosomes in the GnomAD database, including 77,200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15857 hom., cov: 33)
  • Exomes 𝑓: 0.36 (61343 hom.)
• Consequence: NFKBIA NM_020529.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.184

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=-0.71).
• BP6: Variant 14-35401887-C-T is Benign according to our data. Variant chr14-35401887-C-T is described in ClinVar as [Benign]. Clinvar id is 313105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFKBIA	NM_020529.3	c.*126G>A		3_prime_UTR_variant	6/6	ENST00000216797.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFKBIA	ENST00000216797.10	c.*126G>A		3_prime_UTR_variant	6/6	1	NM_020529.3	P1

Frequencies

GnomAD3 genomes AF: 0.442 AC: 67180 AN: 151942 Hom.: 15835 Cov.: 33

Gnomad AFR AF: 0.611

Gnomad AMI AF: 0.209

Gnomad AMR AF: 0.337

Gnomad ASJ AF: 0.400

Gnomad EAS AF: 0.399

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.429

GnomAD4 exome AF: 0.362 AC: 326365 AN: 901312 Hom.: 61343 Cov.: 12 AF XY: 0.366 AC XY: 170900 AN XY: 467516

Gnomad4 AFR exome AF: 0.602

Gnomad4 AMR exome AF: 0.293

Gnomad4 ASJ exome AF: 0.419

Gnomad4 EAS exome AF: 0.352

Gnomad4 SAS exome AF: 0.403

Gnomad4 FIN exome AF: 0.395

Gnomad4 NFE exome AF: 0.349

Gnomad4 OTH exome AF: 0.379

GnomAD4 genome AF: 0.442 AC: 67247 AN: 152060 Hom.: 15857 Cov.: 33 AF XY: 0.439 AC XY: 32650 AN XY: 74298

Gnomad4 AFR AF: 0.611

Gnomad4 AMR AF: 0.337

Gnomad4 ASJ AF: 0.400

Gnomad4 EAS AF: 0.398

Gnomad4 SAS AF: 0.433

Gnomad4 FIN AF: 0.399

Gnomad4 NFE AF: 0.379

Gnomad4 OTH AF: 0.437

Alfa AF: 0.393 Hom.: 6583

Bravo AF: 0.441

Asia WGS AF: 0.422 AC: 1468 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ectodermal dysplasia and immunodeficiency 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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	Invitae	Nov 25, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 34% of patients studied by a panel of primary immunodeficiencies. Number of patients: 32. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

This variant is associated with the following publications: (PMID: 21738780, 23322360) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	14
Dann	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

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: rs696; hg19: chr14-35871093; COSMIC: COSV53754196; COSMIC: COSV53754196;