rs2273650

Positions:

• chr14-35401592-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_020529.3(NFKBIA):​c.*421G>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 0.0257 in 291,100 control chromosomes in the GnomAD database, including 735 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (223 hom., cov: 32)
  • Exomes 𝑓: 0.035 (512 hom.)
• Consequence: NFKBIA NM_020529.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.64

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 14-35401592-C-T is Benign according to our data. Variant chr14-35401592-C-T is described in ClinVar as [Benign]. Clinvar id is 313099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFKBIA	NM_020529.3	c.*421G>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.*421G>A		3_prime_UTR_variant	6/6	1	NM_020529.3	P1

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2598 AN: 152186 Hom.: 222 Cov.: 32

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0315

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.262

Gnomad SAS AF: 0.0715

Gnomad FIN AF: 0.0181

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.0167

GnomAD4 exome AF: 0.0352 AC: 4890 AN: 138796 Hom.: 512 Cov.: 0 AF XY: 0.0365 AC XY: 2542 AN XY: 69592

Gnomad4 AFR exome AF: 0.00194

Gnomad4 AMR exome AF: 0.0445

Gnomad4 ASJ exome AF: 0.00116

Gnomad4 EAS exome AF: 0.259

Gnomad4 SAS exome AF: 0.0738

Gnomad4 FIN exome AF: 0.0122

Gnomad4 NFE exome AF: 0.00134

Gnomad4 OTH exome AF: 0.0190

GnomAD4 genome AF: 0.0170 AC: 2594 AN: 152304 Hom.: 223 Cov.: 32 AF XY: 0.0209 AC XY: 1558 AN XY: 74466

Gnomad4 AFR AF: 0.00192

Gnomad4 AMR AF: 0.0314

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.262

Gnomad4 SAS AF: 0.0714

Gnomad4 FIN AF: 0.0181

Gnomad4 NFE AF: 0.00137

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.00918 Hom.: 27

Bravo AF: 0.0181

Asia WGS AF: 0.186 AC: 645 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ectodermal dysplasia and immunodeficiency 2 Benign:1

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Benign	0.76
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.1

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: rs2273650; hg19: chr14-35870798;