chr14-35401592-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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: 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKBIA	NM_020529.3	c.*421G>A		3_prime_UTR_variant	Exon 6 of 6	ENST00000216797.10	NP_065390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKBIA	ENST00000216797.10	c.*421G>A		3_prime_UTR_variant	Exon 6 of 6	1	NM_020529.3	ENSP00000216797.6

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ectodermal dysplasia and immunodeficiency 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs2273650; hg19: chr14-35870798;