rs696

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is The variant received -16 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_Strong

The NM_020529.3(NFKBIA):c.*126G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.374 (AC=393,612) in the gnomAD database across 1,053,372 control chromosomes, including 77,200 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.604. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

Frequency

Genomes: 𝑓 0.44 ( 15857 hom., cov: 33)

Exomes 𝑓: 0.36 ( 61343 hom. )

Consequence

NFKBIA
NM_020529.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.184

Publications

150 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: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia
ectodermal dysplasia and immune deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

NFKBIA links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_020529.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

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

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

BP6

ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.6044 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_020529.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKBIA	NM_020529.3	MANE Select	c.*126G>A		3_prime_UTR	Exon 6 of 6	NP_065390.1	P25963

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NFKBIA	ENST00000216797.10	TSL:1 MANE Select	c.*126G>A	3_prime_UTR	Exon 6 of 6	ENSP00000216797.6	P25963
NFKBIA	ENST00000860149.1		c.*126G>A	3_prime_UTR	Exon 6 of 6	ENSP00000530208.1
NFKBIA	ENST00000697961.1		c.*495G>A	3_prime_UTR	Exon 5 of 5	ENSP00000513487.1	A0A8V8TLC3

Frequencies

GnomAD3 genomes

AF:

0.442

AC:

67180

AN:

151942

Hom.:

15835

Cov.:

show subpopulations

Gnomad AFR

AF:

0.611

Gnomad AMI

AF:

0.209

Gnomad AMR

AF:

0.337

Gnomad ASJ

AF:

0.400

Gnomad EAS

AF:

0.399

Gnomad SAS

AF:

0.435

Gnomad FIN

AF:

0.399

Gnomad MID

AF:

0.465

Gnomad NFE

AF:

0.379

Gnomad OTH

AF:

0.429

GnomAD4 exome

AF:

0.362

AC:

326365

AN:

901312

Hom.:

61343

Cov.:

AF XY:

0.366

AC XY:

170900

AN XY:

467516

show subpopulations

African (AFR)

AF:

0.602

AC:

11938

AN:

19834

American (AMR)

AF:

0.293

AC:

11186

AN:

38114

Ashkenazi Jewish (ASJ)

AF:

0.419

AC:

9240

AN:

22064

East Asian (EAS)

AF:

0.352

AC:

11894

AN:

33748

South Asian (SAS)

AF:

0.403

AC:

27749

AN:

68908

European-Finnish (FIN)

AF:

0.395

AC:

19391

AN:

49104

Middle Eastern (MID)

AF:

0.396

AC:

1175

AN:

2968

European-Non Finnish (NFE)

AF:

0.349

AC:

218167

AN:

625302

Other (OTH)

AF:

0.379

AC:

15625

AN:

41270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

9409

18817

28226

37634

47043

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4844

9688

14532

19376

24220

<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:

0.442

AC:

67247

AN:

152060

Hom.:

15857

Cov.:

AF XY:

0.439

AC XY:

32650

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.611

AC:

25323

AN:

41464

American (AMR)

AF:

0.337

AC:

5157

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.400

AC:

1388

AN:

3472

East Asian (EAS)

AF:

0.398

AC:

2060

AN:

5174

South Asian (SAS)

AF:

0.433

AC:

2086

AN:

4814

European-Finnish (FIN)

AF:

0.399

AC:

4215

AN:

10564

Middle Eastern (MID)

AF:

0.473

AC:

139

AN:

294

European-Non Finnish (NFE)

AF:

0.379

AC:

25768

AN:

67974

Other (OTH)

AF:

0.437

AC:

920

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1878

3756

5634

7512

9390

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

614

1228

1842

2456

3070

<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:

0.401

Hom.:

10999

Bravo

AF:

0.441

Asia WGS

AF:

0.422

AC:

1468

AN:

3478

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.314

AC:

38553

AN:

122750

Turkish Variome

AF:

0.390

AC:

603

AN:

1546

Hom.:

118

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.414

AC:

3707

AN:

8960

Hom.:

788

ABraOM SABE-WGS-1171

AF:

0.416

AC:

975

AN:

2342

Hom.:

204

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ectodermal dysplasia and immunodeficiency 2 (2)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.81

PhyloP100

-0.18

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over