14-35401995-C-G

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.*18G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,613,102 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (12 hom.)
• Consequence: NFKBIA NM_020529.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.174

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=-0.74).
• BP6: Variant 14-35401995-C-G is Benign according to our data. Variant chr14-35401995-C-G is described in ClinVar as [Benign]. Clinvar id is 313107.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 198 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFKBIA	NM_020529.3	c.*18G>C		3_prime_UTR_variant	6/6	ENST00000216797.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFKBIA	ENST00000216797.10	c.*18G>C		3_prime_UTR_variant	6/6	1	NM_020529.3	P1

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 198 AN: 151838 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000315

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00304

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00170 AC: 426 AN: 251280 Hom.: 3 AF XY: 0.00176 AC XY: 239 AN XY: 135868

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00157

Gnomad FIN exome AF: 0.00236

Gnomad NFE exome AF: 0.00185

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00161 AC: 2349 AN: 1461144 Hom.: 12 Cov.: 31 AF XY: 0.00172 AC XY: 1250 AN XY: 726936

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00474

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00169

Gnomad4 FIN exome AF: 0.00223

Gnomad4 NFE exome AF: 0.00157

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.00130 AC: 198 AN: 151958 Hom.: 1 Cov.: 33 AF XY: 0.00110 AC XY: 82 AN XY: 74272

Gnomad4 AFR AF: 0.000314

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00304

Gnomad4 NFE AF: 0.00154

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00190 Hom.: 0

Bravo AF: 0.00123

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 12, 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	-0.74
Cadd	Benign	14
Dann	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs9333352; hg19: chr14-35871201; COSMIC: COSV104578443; COSMIC: COSV104578443;