rs2233412

Positions:

• chr14-35403783-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_020529.3(NFKBIA):​c.243C>T​(p.Ala81Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,613,646 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (21 hom.)
• Consequence: NFKBIA NM_020529.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.210

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 14-35403783-G-A is Benign according to our data. Variant chr14-35403783-G-A is described in ClinVar as [Benign]. Clinvar id is 313116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.21 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00819 (1248/152302) while in subpopulation AFR AF= 0.0281 (1166/41568). AF 95% confidence interval is 0.0267. There are 14 homozygotes in gnomad4. There are 602 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1248 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFKBIA	NM_020529.3	c.243C>T	p.Ala81Ala	synonymous_variant	2/6	ENST00000216797.10	NP_065390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFKBIA	ENST00000216797.10	c.243C>T	p.Ala81Ala	synonymous_variant	2/6	1	NM_020529.3	ENSP00000216797.6

Frequencies

GnomAD3 genomes AF: 0.00821 AC: 1249 AN: 152184 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00223 AC: 559 AN: 250328 Hom.: 6 AF XY: 0.00151 AC XY: 205 AN XY: 135436

Gnomad AFR exome AF: 0.0273

Gnomad AMR exome AF: 0.000899

Gnomad ASJ exome AF: 0.00658

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.000982

GnomAD4 exome AF: 0.000972 AC: 1421 AN: 1461344 Hom.: 21 Cov.: 31 AF XY: 0.000891 AC XY: 648 AN XY: 726966

Gnomad4 AFR exome AF: 0.0299

Gnomad4 AMR exome AF: 0.000985

Gnomad4 ASJ exome AF: 0.00551

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000935

Gnomad4 OTH exome AF: 0.00190

GnomAD4 genome AF: 0.00819 AC: 1248 AN: 152302 Hom.: 14 Cov.: 32 AF XY: 0.00808 AC XY: 602 AN XY: 74466

Gnomad4 AFR AF: 0.0281

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00536 Hom.: 1

Bravo AF: 0.00932

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
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:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 31, 2017	- -
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	-0.28
CADD	Benign	11
DANN	Uncertain	0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2233412; hg19: chr14-35872989;