14-35401750-C-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_020529.3(NFKBIA):c.*263G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 528,830 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: NFKBIA NM_020529.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0920

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 14-35401750-C-A is Benign according to our data. Variant chr14-35401750-C-A is described in ClinVar as [Benign]. Clinvar id is 313102.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 176 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFKBIA	NM_020529.3	c.*263G>T		3_prime_UTR_variant	6/6	ENST00000216797.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFKBIA	ENST00000216797.10	c.*263G>T		3_prime_UTR_variant	6/6	1	NM_020529.3	P1

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 176 AN: 152030 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00113 AC: 425 AN: 376682 Hom.: 0 Cov.: 3 AF XY: 0.00110 AC XY: 219 AN XY: 198572

Gnomad4 AFR exome AF: 0.000273

Gnomad4 AMR exome AF: 0.000133

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000137

Gnomad4 NFE exome AF: 0.00175

Gnomad4 OTH exome AF: 0.000774

GnomAD4 genome AF: 0.00116 AC: 176 AN: 152148 Hom.: 1 Cov.: 32 AF XY: 0.00101 AC XY: 75 AN XY: 74360

Gnomad4 AFR AF: 0.000723

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00212

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00194 Hom.: 1

Bravo AF: 0.00115

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ectodermal dysplasia and immunodeficiency 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	4.5
Dann	Benign	0.55

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

Publications

LitVar

Other links and lift over

dbSNP: rs11569620; hg19: chr14-35870956;