rs1050851

Positions:

• chr14-35403720-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_020529.3(NFKBIA):​c.306C>T​(p.Ala102=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 1,612,520 control chromosomes in the GnomAD database, including 36,461 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2292 hom., cov: 31)
  • Exomes 𝑓: 0.21 (34169 hom.)
• Consequence: NFKBIA NM_020529.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.194

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 14-35403720-G-A is Benign according to our data. Variant chr14-35403720-G-A is described in ClinVar as [Benign]. Clinvar id is 313115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-35403720-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.194 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFKBIA	NM_020529.3	c.306C>T	p.Ala102=	synonymous_variant	2/6	ENST00000216797.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFKBIA	ENST00000216797.10	c.306C>T	p.Ala102=	synonymous_variant	2/6	1	NM_020529.3	P1

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23536 AN: 152012 Hom.: 2293 Cov.: 31

Gnomad AFR AF: 0.0537

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.0170

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.170

Gnomad MID AF: 0.226

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.151

GnomAD3 exomes AF: 0.166 AC: 41483 AN: 250372 Hom.: 4014 AF XY: 0.172 AC XY: 23296 AN XY: 135340

Gnomad AFR exome AF: 0.0533

Gnomad AMR exome AF: 0.0999

Gnomad ASJ exome AF: 0.188

Gnomad EAS exome AF: 0.0152

Gnomad SAS exome AF: 0.174

Gnomad FIN exome AF: 0.163

Gnomad NFE exome AF: 0.222

Gnomad OTH exome AF: 0.186

GnomAD4 exome AF: 0.209 AC: 305398 AN: 1460388 Hom.: 34169 Cov.: 32 AF XY: 0.208 AC XY: 151440 AN XY: 726512

Gnomad4 AFR exome AF: 0.0526

Gnomad4 AMR exome AF: 0.104

Gnomad4 ASJ exome AF: 0.191

Gnomad4 EAS exome AF: 0.0233

Gnomad4 SAS exome AF: 0.177

Gnomad4 FIN exome AF: 0.169

Gnomad4 NFE exome AF: 0.230

Gnomad4 OTH exome AF: 0.199

GnomAD4 genome AF: 0.155 AC: 23530 AN: 152132 Hom.: 2292 Cov.: 31 AF XY: 0.149 AC XY: 11076 AN XY: 74362

Gnomad4 AFR AF: 0.0537

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.190

Gnomad4 EAS AF: 0.0170

Gnomad4 SAS AF: 0.160

Gnomad4 FIN AF: 0.170

Gnomad4 NFE AF: 0.226

Gnomad4 OTH AF: 0.149

Alfa AF: 0.205 Hom.: 4208

Bravo AF: 0.146

Asia WGS AF: 0.0820 AC: 288 AN: 3478

EpiCase AF: 0.222

EpiControl AF: 0.236

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ectodermal dysplasia and immunodeficiency 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
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 specified Benign:2

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 32% of patients studied by a panel of primary immunodeficiencies. Number of patients: 31. Only high quality variants are reported. -
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 -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	9.7
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1050851; hg19: chr14-35872926; COSMIC: COSV53751737; COSMIC: COSV53751737;