rs2233418

Variant names:

• chr14-35402862-G-A
• rs2233418
• NM_020529.3:c.548-3C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_020529.3(NFKBIA):​c.548-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00709 in 1,613,370 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0072 (56 hom.)
• Consequence: NFKBIA NM_020529.3 splice_region, intron
• Scores: Splicing: ADA: 0.001027
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.17
• Publications: 5 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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 14-35402862-G-A is Benign according to our data. Variant chr14-35402862-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 313112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 953 AD gene.

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.548-3C>T		splice_region 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.548-3C>T		splice_region intron	N/A	ENSP00000216797.6	P25963
	NFKBIA	ENST00000860149.1		c.548-3C>T		splice_region intron	N/A	ENSP00000530208.1
	NFKBIA	ENST00000697961.1		c.548-3C>T		splice_region intron	N/A	ENSP00000513487.1	A0A8V8TLC3

Frequencies

GnomAD3 genomes AF: 0.00628 AC: 953 AN: 151646 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00276

Gnomad ASJ AF: 0.00491

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00292

Gnomad FIN AF: 0.00813

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.00577

GnomAD2 exomes AF: 0.00612 AC: 1532 AN: 250402 AF XY: 0.00612

Gnomad AFR exome AF: 0.00112

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.00807

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00656

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.00490

GnomAD4 exome AF: 0.00718 AC: 10493 AN: 1461606 Hom.: 56 Cov.: 35 AF XY: 0.00719 AC XY: 5226 AN XY: 727118

African (AFR) AF: 0.000866 AC: 29 AN: 33472

American (AMR) AF: 0.00186 AC: 83 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00719 AC: 188 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00279 AC: 241 AN: 86252

European-Finnish (FIN) AF: 0.00720 AC: 384 AN: 53340

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5762

European-Non Finnish (NFE) AF: 0.00827 AC: 9200 AN: 1111850

Other (OTH) AF: 0.00581 AC: 351 AN: 60378

GnomAD4 genome AF: 0.00628 AC: 953 AN: 151764 Hom.: 9 Cov.: 33 AF XY: 0.00597 AC XY: 443 AN XY: 74166

African (AFR) AF: 0.00150 AC: 62 AN: 41378

American (AMR) AF: 0.00275 AC: 42 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00491 AC: 17 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00292 AC: 14 AN: 4790

European-Finnish (FIN) AF: 0.00813 AC: 86 AN: 10576

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0104 AC: 709 AN: 67870

Other (OTH) AF: 0.00571 AC: 12 AN: 2100

Alfa AF: 0.00892 Hom.: 4

Bravo AF: 0.00521

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00905

EpiControl AF: 0.00800

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Ectodermal dysplasia and immunodeficiency 2 (5)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	9.6
DANN	Benign	0.83
PhyloP100		2.2
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		1.8
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0010
dbscSNV1_RF	Benign	0.12
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

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

Other links and lift over

dbSNP: rs2233418;

hg19: chr14-35872068;

COSMIC: COSV53755394;