rs2233415

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr14-35403586-A-G
• chr14-35403586-A-C
• chr14-35403586-A-T

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: 14 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: DEFINITIVE, STRONG Submitted by: ClinGen, 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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKBIA	NM_020529.3	MANE Select	c.336+104T>C		intron	N/A	NP_065390.1	P25963

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKBIA	ENST00000216797.10	TSL:1 MANE Select	c.336+104T>C		intron	N/A	ENSP00000216797.6	P25963
	NFKBIA	ENST00000860149.1		c.336+104T>C		intron	N/A	ENSP00000530208.1
	NFKBIA	ENST00000697961.1		c.336+104T>C		intron	N/A	ENSP00000513487.1	A0A8V8TLC3

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2233415;

hg19: chr14-35872792;

COSMIC: COSV53754807;

COSMIC: COSV53754807;