Genetic Variant NM_031419.4:c.175G>C (chr3-101849803-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_031419.4(NFKBIZ):c.175G>C(p.Ala59Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000759 in 1,318,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. A59T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

NFKBIZ
NM_031419.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.80

Publications

0 publications found

Variant links:

Genes affected

NFKBIZ (HGNC:29805): (NFKB inhibitor zeta) This gene is a member of the ankyrin-repeat family and is induced by lipopolysaccharide (LPS). The C-terminal portion of the encoded product which contains the ankyrin repeats, shares high sequence similarity with the I kappa B family of proteins. The latter are known to play a role in inflammatory responses to LPS by their interaction with NF-B proteins through ankyrin-repeat domains. Studies in mouse indicate that this gene product is one of the nuclear I kappa B proteins and an activator of IL-6 production. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

NFKBIZ Gene-Disease associations (from GenCC):

hereditary nonpolyposis colon cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

NFKBIZ links:

ENSG00000297105 (HGNC:):

ENSG00000297105 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33794084).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKBIZ	NM_031419.4 link	c.175G>C	p.Ala59Pro	missense_variant	Exon 1 of 12	ENST00000326172.9	NP_113607.1	Q9BYH8-1
NFKBIZ	NM_001005474.3 link	c.-11-2282G>C		intron_variant	Intron 2 of 12		NP_001005474.1	Q9BYH8-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKBIZ	ENST00000326172.9 link	c.175G>C	p.Ala59Pro	missense_variant	Exon 1 of 12	1	NM_031419.4	ENSP00000325663.5		Q9BYH8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.59e-7

AC:

AN:

1318278

Hom.:

Cov.:

AF XY:

0.00000154

AC XY:

AN XY:

650406

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26604

American (AMR)

AF:

0.00

AC:

AN:

25142

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23184

East Asian (EAS)

AF:

0.00

AC:

AN:

28232

South Asian (SAS)

AF:

0.00

AC:

AN:

72526

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33462

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3954

European-Non Finnish (NFE)

AF:

9.52e-7

AC:

AN:

1050450

Other (OTH)

AF:

0.00

AC:

AN:

54724

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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

0.11

BayesDel_addAF

Uncertain

0.075

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.066

T;.;T

Eigen

Benign

0.11

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.76

T;T;T

M_CAP

Pathogenic

0.91

MetaRNN

Benign

0.34

T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.8

.;L;L

PhyloP100

1.8

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-4.1

D;N;N

REVEL

Benign

0.15

Sift

Uncertain

0.010

D;D;D

Sift4G

Uncertain

0.033

D;D;D

Polyphen

0.95, 0.95

.;P;P

Vest4

0.20, 0.18

MutPred

0.17

Gain of glycosylation at A59 (P = 0.0171);Gain of glycosylation at A59 (P = 0.0171);Gain of glycosylation at A59 (P = 0.0171);

MVP

0.37

MPC

0.78

ClinPred

0.99

GERP RS

3.1

PromoterAI

0.0080

Neutral

(source)

Varity_R

0.28

gMVP

0.27

Mutation Taster

=76/24

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