chr14-35402754-G-A

Variant names:

• chr14-35402754-G-A
• rs2233419
• NM_020529.3:c.636+17C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020529.3(NFKBIA):​c.636+17C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,613,940 control chromosomes in the GnomAD database, including 26,631 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1899 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24732 hom.)
• Consequence: NFKBIA NM_020529.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.163
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• ectodermal dysplasia and immunodeficiency 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• ectodermal dysplasia and immune deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 14-35402754-G-A is Benign according to our data. Variant chr14-35402754-G-A is described in ClinVar as Benign. ClinVar VariationId is 1166715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020529.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKBIA	NM_020529.3	MANE Select	c.636+17C>T		intron	N/A	NP_065390.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKBIA	ENST00000216797.10	TSL:1 MANE Select	c.636+17C>T		intron	N/A	ENSP00000216797.6
	NFKBIA	ENST00000555371.1	TSL:3	n.195C>T		non_coding_transcript_exon	Exon 2 of 3
	NFKBIA	ENST00000557459.2	TSL:2	n.1041C>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22922 AN: 152060 Hom.: 1899 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.0331

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.190

Gnomad OTH AF: 0.139

GnomAD2 exomes AF: 0.153 AC: 38554 AN: 251316 AF XY: 0.156

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.136

Gnomad ASJ exome AF: 0.0995

Gnomad EAS exome AF: 0.0257

Gnomad FIN exome AF: 0.153

Gnomad NFE exome AF: 0.188

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.180 AC: 263744 AN: 1461762 Hom.: 24732 Cov.: 37 AF XY: 0.179 AC XY: 130388 AN XY: 727190

African (AFR) AF: 0.105 AC: 3507 AN: 33478

American (AMR) AF: 0.135 AC: 6015 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 2719 AN: 26134

East Asian (EAS) AF: 0.0369 AC: 1466 AN: 39698

South Asian (SAS) AF: 0.161 AC: 13878 AN: 86254

European-Finnish (FIN) AF: 0.158 AC: 8425 AN: 53414

Middle Eastern (MID) AF: 0.164 AC: 943 AN: 5766

European-Non Finnish (NFE) AF: 0.195 AC: 216616 AN: 1111914

Other (OTH) AF: 0.168 AC: 10175 AN: 60390

GnomAD4 genome AF: 0.151 AC: 22940 AN: 152178 Hom.: 1899 Cov.: 32 AF XY: 0.148 AC XY: 10978 AN XY: 74404

African (AFR) AF: 0.106 AC: 4407 AN: 41498

American (AMR) AF: 0.143 AC: 2192 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 358 AN: 3472

East Asian (EAS) AF: 0.0331 AC: 172 AN: 5190

South Asian (SAS) AF: 0.149 AC: 721 AN: 4824

European-Finnish (FIN) AF: 0.159 AC: 1682 AN: 10590

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.190 AC: 12927 AN: 67998

Other (OTH) AF: 0.138 AC: 292 AN: 2114

Alfa AF: 0.168 Hom.: 3968

Bravo AF: 0.147

Asia WGS AF: 0.0990 AC: 347 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 26% of patients studied by a panel of primary immunodeficiencies. Number of patients: 25. Only high quality variants are reported.

Ectodermal dysplasia and immunodeficiency 2 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.4
DANN	Benign	0.72
PhyloP100		0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2233419; hg19: chr14-35871960; COSMIC: COSV53751722; COSMIC: COSV53751722;