rs2273650

Variant names:

• chr14-35401592-C-T
• rs2273650
• NM_020529.3:c.*421G>A

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.*421G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0257 in 291,100 control chromosomes in the GnomAD database, including 735 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (223 hom., cov: 32)
  • Exomes 𝑓: 0.035 (512 hom.)
• Consequence: NFKBIA NM_020529.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.64
• Publications: 16 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 14-35401592-C-T is Benign according to our data. Variant chr14-35401592-C-T is described in ClinVar as Benign. ClinVar VariationId is 313099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.251 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.*421G>A		3_prime_UTR	Exon 6 of 6	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.*421G>A		3_prime_UTR	Exon 6 of 6	ENSP00000216797.6	P25963
	NFKBIA	ENST00000860149.1		c.*421G>A		3_prime_UTR	Exon 6 of 6	ENSP00000530208.1
	NFKBIA	ENST00000697961.1		c.*790G>A		3_prime_UTR	Exon 5 of 5	ENSP00000513487.1	A0A8V8TLC3

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2598 AN: 152186 Hom.: 222 Cov.: 32

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0315

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.262

Gnomad SAS AF: 0.0715

Gnomad FIN AF: 0.0181

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.0167

GnomAD4 exome AF: 0.0352 AC: 4890 AN: 138796 Hom.: 512 Cov.: 0 AF XY: 0.0365 AC XY: 2542 AN XY: 69592

African (AFR) AF: 0.00194 AC: 9 AN: 4646

American (AMR) AF: 0.0445 AC: 268 AN: 6022

Ashkenazi Jewish (ASJ) AF: 0.00116 AC: 7 AN: 6048

East Asian (EAS) AF: 0.259 AC: 3423 AN: 13226

South Asian (SAS) AF: 0.0738 AC: 854 AN: 11568

European-Finnish (FIN) AF: 0.0122 AC: 30 AN: 2454

Middle Eastern (MID) AF: 0.0114 AC: 7 AN: 612

European-Non Finnish (NFE) AF: 0.00134 AC: 114 AN: 84856

Other (OTH) AF: 0.0190 AC: 178 AN: 9364

GnomAD4 genome AF: 0.0170 AC: 2594 AN: 152304 Hom.: 223 Cov.: 32 AF XY: 0.0209 AC XY: 1558 AN XY: 74466

African (AFR) AF: 0.00192 AC: 80 AN: 41572

American (AMR) AF: 0.0314 AC: 480 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.262 AC: 1358 AN: 5180

South Asian (SAS) AF: 0.0714 AC: 345 AN: 4834

European-Finnish (FIN) AF: 0.0181 AC: 192 AN: 10608

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00137 AC: 93 AN: 68028

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.00815 Hom.: 27

Bravo AF: 0.0181

Asia WGS AF: 0.186 AC: 645 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Benign	0.76
PhyloP100		2.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.1
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

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

Other links and lift over

dbSNP: rs2273650;

hg19: chr14-35870798;