rs2233418

Positions:

• chr14-35402862-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_020529.3(NFKBIA):​c.548-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00709 in 1,613,370 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0072 (56 hom.)
• Consequence: NFKBIA NM_020529.3 splice_region, intron
• Scores: Splicing: ADA: 0.001027
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.17

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]

NFKBIA (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 14-35402862-G-A is Benign according to our data. Variant chr14-35402862-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 313112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-35402862-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 953 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFKBIA	NM_020529.3	c.548-3C>T		splice_region_variant, intron_variant		ENST00000216797.10	NP_065390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFKBIA	ENST00000216797.10	c.548-3C>T		splice_region_variant, intron_variant		1	NM_020529.3	ENSP00000216797.6

Frequencies

GnomAD3 genomes AF: 0.00628 AC: 953 AN: 151646 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00276

Gnomad ASJ AF: 0.00491

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00292

Gnomad FIN AF: 0.00813

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.00577

GnomAD3 exomes AF: 0.00612 AC: 1532 AN: 250402 Hom.: 7 AF XY: 0.00612 AC XY: 829 AN XY: 135424

Gnomad AFR exome AF: 0.00112

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.00807

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00242

Gnomad FIN exome AF: 0.00656

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.00490

GnomAD4 exome AF: 0.00718 AC: 10493 AN: 1461606 Hom.: 56 Cov.: 35 AF XY: 0.00719 AC XY: 5226 AN XY: 727118

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.00186

Gnomad4 ASJ exome AF: 0.00719

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00279

Gnomad4 FIN exome AF: 0.00720

Gnomad4 NFE exome AF: 0.00827

Gnomad4 OTH exome AF: 0.00581

GnomAD4 genome AF: 0.00628 AC: 953 AN: 151764 Hom.: 9 Cov.: 33 AF XY: 0.00597 AC XY: 443 AN XY: 74166

Gnomad4 AFR AF: 0.00150

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.00491

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00292

Gnomad4 FIN AF: 0.00813

Gnomad4 NFE AF: 0.0104

Gnomad4 OTH AF: 0.00571

Alfa AF: 0.00892 Hom.: 4

Bravo AF: 0.00521

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00905

EpiControl AF: 0.00800

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ectodermal dysplasia and immunodeficiency 2 Benign:4

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 30, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2024

NFKBIA: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	9.6
DANN	Benign	0.83
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0010
dbscSNV1_RF	Benign	0.12
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: rs2233418; hg19: chr14-35872068; COSMIC: COSV53755394; COSMIC: COSV53755394;