rs1050851

Variant names:

• chr14-35403720-G-A
• rs1050851
• NM_020529.3:c.306C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_020529.3(NFKBIA):​c.306C>T​(p.Ala102Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 1,612,520 control chromosomes in the GnomAD database, including 36,461 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2292 hom., cov: 31)
  • Exomes 𝑓: 0.21 (34169 hom.)
• Consequence: NFKBIA NM_020529.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.194
• Publications: 33 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

ENSG00000310246 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 14-35403720-G-A is Benign according to our data. Variant chr14-35403720-G-A is described in ClinVar as Benign. ClinVar VariationId is 313115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.194 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.223 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKBIA	NM_020529.3	MANE Select	c.306C>T	p.Ala102Ala	synonymous	Exon 2 of 6	NP_065390.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKBIA	ENST00000216797.10	TSL:1 MANE Select	c.306C>T	p.Ala102Ala	synonymous	Exon 2 of 6	ENSP00000216797.6
	NFKBIA	ENST00000697961.1		c.306C>T	p.Ala102Ala	synonymous	Exon 2 of 5	ENSP00000513487.1
	NFKBIA	ENST00000553342.2	TSL:5	c.234C>T	p.Ala78Ala	synonymous	Exon 3 of 7	ENSP00000451281.2

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23536 AN: 152012 Hom.: 2293 Cov.: 31

Gnomad AFR AF: 0.0537

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.0170

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.170

Gnomad MID AF: 0.226

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.151

GnomAD2 exomes AF: 0.166 AC: 41483 AN: 250372 AF XY: 0.172

Gnomad AFR exome AF: 0.0533

Gnomad AMR exome AF: 0.0999

Gnomad ASJ exome AF: 0.188

Gnomad EAS exome AF: 0.0152

Gnomad FIN exome AF: 0.163

Gnomad NFE exome AF: 0.222

Gnomad OTH exome AF: 0.186

GnomAD4 exome AF: 0.209 AC: 305398 AN: 1460388 Hom.: 34169 Cov.: 32 AF XY: 0.208 AC XY: 151440 AN XY: 726512

African (AFR) AF: 0.0526 AC: 1761 AN: 33476

American (AMR) AF: 0.104 AC: 4647 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 4986 AN: 26120

East Asian (EAS) AF: 0.0233 AC: 926 AN: 39692

South Asian (SAS) AF: 0.177 AC: 15277 AN: 86152

European-Finnish (FIN) AF: 0.169 AC: 9041 AN: 53378

Middle Eastern (MID) AF: 0.210 AC: 1208 AN: 5754

European-Non Finnish (NFE) AF: 0.230 AC: 255526 AN: 1110824

Other (OTH) AF: 0.199 AC: 12026 AN: 60332

GnomAD4 genome AF: 0.155 AC: 23530 AN: 152132 Hom.: 2292 Cov.: 31 AF XY: 0.149 AC XY: 11076 AN XY: 74362

African (AFR) AF: 0.0537 AC: 2229 AN: 41526

American (AMR) AF: 0.137 AC: 2091 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 659 AN: 3470

East Asian (EAS) AF: 0.0170 AC: 88 AN: 5162

South Asian (SAS) AF: 0.160 AC: 774 AN: 4826

European-Finnish (FIN) AF: 0.170 AC: 1802 AN: 10586

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.226 AC: 15386 AN: 67954

Other (OTH) AF: 0.149 AC: 314 AN: 2106

Alfa AF: 0.196 Hom.: 5392

Bravo AF: 0.146

Asia WGS AF: 0.0820 AC: 288 AN: 3478

EpiCase AF: 0.222

EpiControl AF: 0.236

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Ectodermal dysplasia and immunodeficiency 2 (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	9.7
DANN	Benign	0.89
PhyloP100		-0.19
PromoterAI		-0.067	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1050851; hg19: chr14-35872926; COSMIC: COSV53751737; COSMIC: COSV53751737;