14-35402888-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020529.3(NFKBIA):c.548-29G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 1,597,270 control chromosomes in the GnomAD database, including 25,578 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1639 hom., cov: 32)

Exomes 𝑓: 0.18 ( 23939 hom. )

Consequence

NFKBIA
NM_020529.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.415

Publications

13 publications found

Variant links:

COSMIC-nc: COSV53751730

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 14-35402888-C-T is Benign according to our data. Variant chr14-35402888-C-T is described in CliVar as Benign. Clinvar id is 1260146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-35402888-C-T is described in CliVar as Benign. Clinvar id is 1260146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-35402888-C-T is described in CliVar as Benign. Clinvar id is 1260146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-35402888-C-T is described in CliVar as Benign. Clinvar id is 1260146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-35402888-C-T is described in CliVar as Benign. Clinvar id is 1260146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-35402888-C-T is described in CliVar as Benign. Clinvar id is 1260146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-35402888-C-T is described in CliVar as Benign. Clinvar id is 1260146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-35402888-C-T is described in CliVar as Benign. Clinvar id is 1260146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-35402888-C-T is described in CliVar as Benign. Clinvar id is 1260146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKBIA	NM_020529.3 link	c.548-29G>A		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.548-29G>A		intron_variant	Intron 3 of 5	1	NM_020529.3	ENSP00000216797.6		P25963

Frequencies

GnomAD3 genomes

AF:

0.134

AC:

20306

AN:

152096

Hom.:

1640

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0610

Gnomad AMI

AF:

0.166

Gnomad AMR

AF:

0.105

Gnomad ASJ

AF:

0.106

Gnomad EAS

AF:

0.0138

Gnomad SAS

AF:

0.148

Gnomad FIN

AF:

0.159

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.189

Gnomad OTH

AF:

0.126

GnomAD2 exomes

AF:

0.141

AC:

34599

AN:

245658

AF XY:

0.146

show subpopulations

Gnomad AFR exome

AF:

0.0631

Gnomad AMR exome

AF:

0.0788

Gnomad ASJ exome

AF:

0.101

Gnomad EAS exome

AF:

0.0107

Gnomad FIN exome

AF:

0.153

Gnomad NFE exome

AF:

0.188

Gnomad OTH exome

AF:

0.159

GnomAD4 exome

AF:

0.177

AC:

255406

AN:

1445056

Hom.:

23939

Cov.:

AF XY:

0.176

AC XY:

126751

AN XY:

719858

show subpopulations

African (AFR)

AF:

0.0610

AC:

2018

AN:

33082

American (AMR)

AF:

0.0819

AC:

3642

AN:

44472

Ashkenazi Jewish (ASJ)

AF:

0.106

AC:

2766

AN:

26030

East Asian (EAS)

AF:

0.0175

AC:

691

AN:

39562

South Asian (SAS)

AF:

0.159

AC:

13686

AN:

85858

European-Finnish (FIN)

AF:

0.158

AC:

8359

AN:

53052

Middle Eastern (MID)

AF:

0.159

AC:

901

AN:

5656

European-Non Finnish (NFE)

AF:

0.195

AC:

213561

AN:

1097544

Other (OTH)

AF:

0.164

AC:

9782

AN:

59800

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

10594

21187

31781

42374

52968

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7332

14664

21996

29328

36660

<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:

0.133

AC:

20309

AN:

152214

Hom.:

1639

Cov.:

AF XY:

0.130

AC XY:

9677

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0611

AC:

2538

AN:

41524

American (AMR)

AF:

0.105

AC:

1606

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.106

AC:

367

AN:

3472

East Asian (EAS)

AF:

0.0139

AC:

AN:

5192

South Asian (SAS)

AF:

0.148

AC:

714

AN:

4830

European-Finnish (FIN)

AF:

0.159

AC:

1687

AN:

10604

Middle Eastern (MID)

AF:

0.146

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.189

AC:

12868

AN:

67986

Other (OTH)

AF:

0.125

AC:

263

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

901

1802

2702

3603

4504

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

228

456

684

912

1140

<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:

0.139

Hom.:

639

Bravo

AF:

0.126

Asia WGS

AF:

0.0770

AC:

272

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 19, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 25% of patients studied by a panel of primary immunodeficiencies. Number of patients: 24. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

1.6

(source)

DANN

Benign

0.77

PhyloP100

-0.41

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over