14-35403586-A-G

Variant names:

• chr14-35403586-A-G
• rs2233415
• NM_020529.3:c.336+104T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_020529.3(NFKBIA):​c.336+104T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.732 in 885,522 control chromosomes in the GnomAD database, including 240,882 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (35846 hom., cov: 31)
  • Exomes 𝑓: 0.74 (205036 hom.)
• Consequence: NFKBIA NM_020529.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.962
• Publications: 13 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

ENSG00000310246 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 14-35403586-A-G is Benign according to our data. Variant chr14-35403586-A-G is described in ClinVar as [Benign]. Clinvar id is 1283234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKBIA	NM_020529.3	c.336+104T>C		intron_variant	Intron 2 of 5	ENST00000216797.10	NP_065390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKBIA	ENST00000216797.10	c.336+104T>C		intron_variant	Intron 2 of 5	1	NM_020529.3	ENSP00000216797.6

Frequencies

GnomAD3 genomes AF: 0.673 AC: 102260 AN: 151912 Hom.: 35815 Cov.: 31

Gnomad AFR AF: 0.472

Gnomad AMI AF: 0.706

Gnomad AMR AF: 0.729

Gnomad ASJ AF: 0.647

Gnomad EAS AF: 0.640

Gnomad SAS AF: 0.831

Gnomad FIN AF: 0.831

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.752

Gnomad OTH AF: 0.646

GnomAD4 exome AF: 0.744 AC: 545488 AN: 733492 Hom.: 205036 Cov.: 10 AF XY: 0.748 AC XY: 289117 AN XY: 386288

African (AFR) AF: 0.463 AC: 8943 AN: 19318

American (AMR) AF: 0.789 AC: 27649 AN: 35032

Ashkenazi Jewish (ASJ) AF: 0.656 AC: 13827 AN: 21082

East Asian (EAS) AF: 0.618 AC: 20677 AN: 33448

South Asian (SAS) AF: 0.839 AC: 55684 AN: 66372

European-Finnish (FIN) AF: 0.818 AC: 39512 AN: 48280

Middle Eastern (MID) AF: 0.650 AC: 2880 AN: 4434

European-Non Finnish (NFE) AF: 0.746 AC: 350306 AN: 469272

Other (OTH) AF: 0.717 AC: 26010 AN: 36254

GnomAD4 genome AF: 0.673 AC: 102343 AN: 152030 Hom.: 35846 Cov.: 31 AF XY: 0.679 AC XY: 50469 AN XY: 74306

African (AFR) AF: 0.473 AC: 19590 AN: 41428

American (AMR) AF: 0.729 AC: 11138 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.647 AC: 2245 AN: 3470

East Asian (EAS) AF: 0.640 AC: 3289 AN: 5142

South Asian (SAS) AF: 0.831 AC: 4003 AN: 4818

European-Finnish (FIN) AF: 0.831 AC: 8807 AN: 10594

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.752 AC: 51091 AN: 67980

Other (OTH) AF: 0.649 AC: 1371 AN: 2112

Alfa AF: 0.690 Hom.: 12033

Bravo AF: 0.654

Asia WGS AF: 0.757 AC: 2633 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

Nov 12, 2018

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 83% of patients studied by a panel of primary immunodeficiencies. Number of patients: 80. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.057
DANN	Benign	0.48
PhyloP100		-0.96
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)		0.010		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: rs2233415; hg19: chr14-35872792; COSMIC: COSV53754807; COSMIC: COSV53754807;