Genetic Variant NFKBIA:p.Thr146Ser (chr14-35403260-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_020529.3(NFKBIA):c.437C>G(p.Thr146Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T146I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

NFKBIA
NM_020529.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.73

Publications

0 publications found

Variant links:

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

NFKBIA links:

ENSG00000310246 (HGNC:):

ENSG00000310246 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.764

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKBIA	NM_020529.3 link	c.437C>G	p.Thr146Ser	missense_variant	Exon 3 of 6	ENST00000216797.10	NP_065390.1	P25963

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKBIA	ENST00000216797.10 link	c.437C>G	p.Thr146Ser	missense_variant	Exon 3 of 6	1	NM_020529.3	ENSP00000216797.6		P25963

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461328

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726958

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5326

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;T;.

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.76

T;D;T

M_CAP

Benign

0.021

MetaRNN

Pathogenic

0.76

D;D;D

MetaSVM

Benign

-0.42

MutationAssessor

Uncertain

2.9

M;.;.

PhyloP100

7.7

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.1

D;D;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.021

D;D;D

Sift4G

Uncertain

0.032

D;D;T

Polyphen

0.93

P;D;.

Vest4

0.85

MutPred

0.61

Gain of catalytic residue at N145 (P = 2e-04);Gain of catalytic residue at N145 (P = 2e-04);.;

MVP

0.72

MPC

1.2

ClinPred

0.99

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.44

gMVP

0.32

Mutation Taster

=57/43

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over