Genetic Variant NM_003998.4:c.1143T>C (chr4-102593501-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003998.4(NFKB1):c.1143T>C(p.Ala381Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.932 in 1,613,432 control chromosomes in the GnomAD database, including 701,115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.94 ( 67896 hom., cov: 30)

Exomes 𝑓: 0.93 ( 633219 hom. )

Consequence

NFKB1
NM_003998.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -7.17

Publications

38 publications found

Variant links:

Genes affected

NFKB1 (HGNC:7794): (nuclear factor kappa B subunit 1) This gene encodes a 105 kD protein which can undergo cotranslational processing by the 26S proteasome to produce a 50 kD protein. The 105 kD protein is a Rel protein-specific transcription inhibitor and the 50 kD protein is a DNA binding subunit of the NF-kappa-B (NFKB) protein complex. NFKB is a transcription regulator that is activated by various intra- and extra-cellular stimuli such as cytokines, oxidant-free radicals, ultraviolet irradiation, and bacterial or viral products. Activated NFKB translocates into the nucleus and stimulates the expression of genes involved in a wide variety of biological functions. Inappropriate activation of NFKB has been associated with a number of inflammatory diseases while persistent inhibition of NFKB leads to inappropriate immune cell development or delayed cell growth. NFKB is a critical regulator of the immediate-early response to viral infection. Alternative splicing results in multiple transcript variants encoding different isoforms, at least one of which is proteolytically processed. [provided by RefSeq, Aug 2020]

NFKB1 Gene-Disease associations (from GenCC):

immunodeficiency, common variable, 12
Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
common variable immunodeficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

NFKB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant 4-102593501-T-C is Benign according to our data. Variant chr4-102593501-T-C is described in ClinVar as Benign. ClinVar VariationId is 1170076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-7.16 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.978 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003998.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NFKB1	NM_003998.4	MANE Select	c.1143T>C	p.Ala381Ala	synonymous	Exon 12 of 24	NP_003989.2
NFKB1	NM_001382625.1		c.1143T>C	p.Ala381Ala	synonymous	Exon 13 of 25	NP_001369554.1	P19838-2
NFKB1	NM_001382626.1		c.1143T>C	p.Ala381Ala	synonymous	Exon 13 of 25	NP_001369555.1	P19838-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NFKB1	ENST00000226574.9	TSL:1 MANE Select	c.1143T>C	p.Ala381Ala	synonymous	Exon 12 of 24	ENSP00000226574.4	P19838-2
NFKB1	ENST00000394820.8	TSL:1	c.1140T>C	p.Ala380Ala	synonymous	Exon 12 of 24	ENSP00000378297.4	P19838-1
NFKB1	ENST00000505458.5	TSL:1	c.1140T>C	p.Ala380Ala	synonymous	Exon 12 of 24	ENSP00000424790.1	P19838-1

Frequencies

GnomAD3 genomes

AF:

0.944

AC:

143529

AN:

152056

Hom.:

67832

Cov.:

show subpopulations

Gnomad AFR

AF:

0.986

Gnomad AMI

AF:

0.977

Gnomad AMR

AF:

0.934

Gnomad ASJ

AF:

0.893

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.985

Gnomad FIN

AF:

0.930

Gnomad MID

AF:

0.921

Gnomad NFE

AF:

0.918

Gnomad OTH

AF:

0.934

GnomAD2 exomes

AF:

0.940

AC:

236090

AN:

251212

AF XY:

0.940

show subpopulations

Gnomad AFR exome

AF:

0.988

Gnomad AMR exome

AF:

0.956

Gnomad ASJ exome

AF:

0.885

Gnomad EAS exome

AF:

0.999

Gnomad FIN exome

AF:

0.931

Gnomad NFE exome

AF:

0.914

Gnomad OTH exome

AF:

0.925

GnomAD4 exome

AF:

0.931

AC:

1359951

AN:

1461258

Hom.:

633219

Cov.:

AF XY:

0.932

AC XY:

677287

AN XY:

726988

show subpopulations

African (AFR)

AF:

0.989

AC:

33084

AN:

33466

American (AMR)

AF:

0.953

AC:

42620

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.889

AC:

23211

AN:

26106

East Asian (EAS)

AF:

1.00

AC:

39676

AN:

39686

South Asian (SAS)

AF:

0.984

AC:

84865

AN:

86222

European-Finnish (FIN)

AF:

0.928

AC:

49575

AN:

53406

Middle Eastern (MID)

AF:

0.933

AC:

5373

AN:

5758

European-Non Finnish (NFE)

AF:

0.922

AC:

1025243

AN:

1111528

Other (OTH)

AF:

0.933

AC:

56304

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

4593

9186

13780

18373

22966

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21548

43096

64644

86192

107740

<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:

0.944

AC:

143652

AN:

152174

Hom.:

67896

Cov.:

AF XY:

0.946

AC XY:

70375

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.986

AC:

40919

AN:

41508

American (AMR)

AF:

0.935

AC:

14279

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.893

AC:

3100

AN:

3470

East Asian (EAS)

AF:

1.00

AC:

5174

AN:

5176

South Asian (SAS)

AF:

0.985

AC:

4754

AN:

4824

European-Finnish (FIN)

AF:

0.930

AC:

9838

AN:

10574

Middle Eastern (MID)

AF:

0.918

AC:

270

AN:

294

European-Non Finnish (NFE)

AF:

0.918

AC:

62452

AN:

68024

Other (OTH)

AF:

0.934

AC:

1975

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

409

818

1226

1635

2044

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

912

1824

2736

3648

4560

<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:

0.925

Hom.:

48024

Bravo

AF:

0.943

Asia WGS

AF:

0.991

AC:

3445

AN:

3478

EpiCase

AF:

0.915

EpiControl

AF:

0.910

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Immunodeficiency, common variable, 12 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.094

(source)

DANN

Benign

0.27

PhyloP100

-7.2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over