NM_020529.3:c.548-3C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_020529.3(NFKBIA):c.548-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00709 in 1,613,370 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0063 ( 9 hom., cov: 33)

Exomes 𝑓: 0.0072 ( 56 hom. )

Consequence

NFKBIA
NM_020529.3 splice_region, intron

Scores

Splicing: ADA: 0.001027

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.17

Publications

5 publications found

Variant links:

COSMIC-nc: COSV53755394

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 14-35402862-G-A is Benign according to our data. Variant chr14-35402862-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 313112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-35402862-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 313112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-35402862-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 313112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-35402862-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 313112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-35402862-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 313112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-35402862-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 313112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-35402862-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 313112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-35402862-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 313112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-35402862-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 313112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 953 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKBIA	NM_020529.3 link	c.548-3C>T		splice_region_variant, intron_variant	Intron 3 of 5	ENST00000216797.10	NP_065390.1	P25963

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKBIA	ENST00000216797.10 link	c.548-3C>T		splice_region_variant, intron_variant	Intron 3 of 5	1	NM_020529.3	ENSP00000216797.6		P25963

Frequencies

GnomAD3 genomes

AF:

0.00628

AC:

953

AN:

151646

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00276

Gnomad ASJ

AF:

0.00491

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00292

Gnomad FIN

AF:

0.00813

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0104

Gnomad OTH

AF:

0.00577

GnomAD2 exomes

AF:

0.00612

AC:

1532

AN:

250402

AF XY:

0.00612

show subpopulations

Gnomad AFR exome

AF:

0.00112

Gnomad AMR exome

AF:

0.00148

Gnomad ASJ exome

AF:

0.00807

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00656

Gnomad NFE exome

AF:

0.0101

Gnomad OTH exome

AF:

0.00490

GnomAD4 exome

AF:

0.00718

AC:

10493

AN:

1461606

Hom.:

Cov.:

AF XY:

0.00719

AC XY:

5226

AN XY:

727118

show subpopulations

African (AFR)

AF:

0.000866

AC:

AN:

33472

American (AMR)

AF:

0.00186

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00719

AC:

188

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00279

AC:

241

AN:

86252

European-Finnish (FIN)

AF:

0.00720

AC:

384

AN:

53340

Middle Eastern (MID)

AF:

0.00295

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00827

AC:

9200

AN:

1111850

Other (OTH)

AF:

0.00581

AC:

351

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

606

1212

1818

2424

3030

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

290

580

870

1160

1450

<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

AF:

0.00628

AC:

953

AN:

151764

Hom.:

Cov.:

AF XY:

0.00597

AC XY:

443

AN XY:

74166

show subpopulations

African (AFR)

AF:

0.00150

AC:

AN:

41378

American (AMR)

AF:

0.00275

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00491

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5140

South Asian (SAS)

AF:

0.00292

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.00813

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0104

AC:

709

AN:

67870

Other (OTH)

AF:

0.00571

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

108

161

215

269

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00892

Hom.:

Bravo

AF:

0.00521

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00905

EpiControl

AF:

0.00800

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ectodermal dysplasia and immunodeficiency 2

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 30, 2015

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NFKBIA: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

9.6

(source)

DANN

Benign

0.83

PhyloP100

2.2

RBP_binding_hub_radar

0.67

RBP_regulation_power_radar

1.8

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0010

dbscSNV1_RF

Benign

0.12

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over