NM_020529.3:c.32G>T

Variant names:

• chr14-35404613-C-A
• rs121913664
• NM_020529.3:c.32G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_020529.3(NFKBIA):​c.32G>T​(p.Trp11Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,405,254 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: NFKBIA NM_020529.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.06
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a region_of_interest Disordered (size 38) in uniprot entity IKBA_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_020529.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20078954).

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.32G>T	p.Trp11Leu	missense	Exon 1 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.32G>T	p.Trp11Leu	missense	Exon 1 of 6	ENSP00000216797.6
	NFKBIA	ENST00000697961.1		c.32G>T	p.Trp11Leu	missense	Exon 1 of 5	ENSP00000513487.1
	NFKBIA	ENST00000553342.2	TSL:5	c.32G>T	p.Trp11Leu	missense	Exon 1 of 7	ENSP00000451281.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1405254 Hom.: 0 Cov.: 34 AF XY: 0.00000144 AC XY: 1 AN XY: 696620

African (AFR) AF: 0.00 AC: 0 AN: 29982

American (AMR) AF: 0.00 AC: 0 AN: 37502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24940

East Asian (EAS) AF: 0.00 AC: 0 AN: 34314

South Asian (SAS) AF: 0.00 AC: 0 AN: 79780

European-Finnish (FIN) AF: 0.0000203 AC: 1 AN: 49226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085664

Other (OTH) AF: 0.00 AC: 0 AN: 58170

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.81	L
PhyloP100		2.1
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.030	N
REVEL	Uncertain	0.30
Sift	Benign	0.53	T
Sift4G	Benign	0.68	T
Polyphen		0.067	B
Vest4		0.56
MutPred		0.43		Gain of catalytic residue at M13 (P = 0.0393)
MVP		0.77
MPC		0.72
ClinPred		0.18	T
GERP RS		3.1
PromoterAI		-0.032	Neutral
Varity_R		0.11
gMVP		0.20
Mutation Taster		=97/3	polymorphism

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: rs121913664; hg19: chr14-35873819;