14-35403260-G-T

Position:

• chr14-35403260-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020529.3(NFKBIA):​c.437C>A​(p.Thr146Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: 6.8e-7 (0 hom.)
• Consequence: NFKBIA NM_020529.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.73

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFKBIA	NM_020529.3	c.437C>A	p.Thr146Asn	missense_variant	3/6	ENST00000216797.10	NP_065390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFKBIA	ENST00000216797.10	c.437C>A	p.Thr146Asn	missense_variant	3/6	1	NM_020529.3	ENSP00000216797.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461328 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726958

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T;T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	0.067	D
MutationAssessor	Pathogenic	3.2	M;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.94
MutPred		0.59		Gain of catalytic residue at N145 (P = 6e-04);Gain of catalytic residue at N145 (P = 6e-04);.;
MVP		0.77
MPC		1.3
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.68
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs753691609; hg19: chr14-35872466;