rs5029941

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001270508.2(TNFAIP3):c.374C>T(p.Ala125Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000935 in 1,614,222 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0053 ( 8 hom., cov: 33)

Exomes 𝑓: 0.00048 ( 7 hom. )

Consequence

TNFAIP3
NM_001270508.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1O:1

Conservation

PhyloP100: 2.81

Publications

28 publications found

Variant links:

Genes affected

TNFAIP3 (HGNC:11896): (TNF alpha induced protein 3) This gene was identified as a gene whose expression is rapidly induced by the tumor necrosis factor (TNF). The protein encoded by this gene is a zinc finger protein and ubiqitin-editing enzyme, and has been shown to inhibit NF-kappa B activation as well as TNF-mediated apoptosis. The encoded protein, which has both ubiquitin ligase and deubiquitinase activities, is involved in the cytokine-mediated immune and inflammatory responses. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2012]

TNFAIP3 Gene-Disease associations (from GenCC):

autoinflammatory syndrome, familial, Behcet-like 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
hereditary pediatric Behçet-like disease
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
systemic lupus erythematosus
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

TNFAIP3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010955274).

BP6

Variant 6-137874923-C-T is Benign according to our data. Variant chr6-137874923-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135332.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00528 (805/152330) while in subpopulation AFR AF = 0.0184 (764/41570). AF 95% confidence interval is 0.0173. There are 8 homozygotes in GnomAd4. There are 380 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 805 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFAIP3	NM_001270508.2 link	c.374C>T	p.Ala125Val	missense_variant	Exon 3 of 9	ENST00000612899.5	NP_001257437.1	P21580

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFAIP3	ENST00000612899.5 link	c.374C>T	p.Ala125Val	missense_variant	Exon 3 of 9	5	NM_001270508.2	ENSP00000481570.1		P21580

Frequencies

GnomAD3 genomes

AF:

0.00528

AC:

804

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0184

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00222

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00120

AC:

303

AN:

251472

AF XY:

0.000876

show subpopulations

Gnomad AFR exome

AF:

0.0169

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000977

GnomAD4 exome

AF:

0.000482

AC:

704

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

313

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0173

AC:

578

AN:

33480

American (AMR)

AF:

0.000693

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000243

AC:

AN:

1112012

Other (OTH)

AF:

0.00101

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

127

170

212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00528

AC:

805

AN:

152330

Hom.:

Cov.:

AF XY:

0.00510

AC XY:

380

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0184

AC:

764

AN:

41570

American (AMR)

AF:

0.00222

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68032

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

125

166

208

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:

0.00206

Hom.:

Bravo

AF:

0.00570

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0163

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00166

AC:

201

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Other:1

Oct 13, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Autoinflammatory syndrome, familial, Behcet-like 1

Uncertain:1

Aug 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The TNFAIP3 c.374C>T; p.Ala125Val variant (rs5029941), to our knowledge, has not been reported in individuals with Behcet-like autoinflammatory syndrome but has been reported to mediate risk for other inflammatory related disorders (Lodolce 2010). Functional analyses of the variant protein show diminished deubiquitination and degradation activity, although it is unclear whether this results in increased or decreased inflammation (Lodolce 2010). This variant is also reported in ClinVar (Variation ID: 135332). This variant is found in the African population with an allele frequency of 1.7% (434/24970 alleles, including 4 homozygotes) in the Genome Aggregation Database v2.1.1. The alanine at codon 125 is moderately conserved, but computational analyses predict that this variant is neutral (REVEL: 0.078). Although the population frequency of this variant is relatively high, the possibility of reduced penetrance or a mild effect cannot be excluded. Therefore, due to a lack of clinical and functional data, the significance of this variant cannot be determined with certainty. Reference Lodolce JP et al. African-derived genetic polymorphisms in TNFAIP3 mediate risk for autoimmunity. J Immunol. 2010 Jun 15;184(12):7001-9. PMID: 20483768. -

not provided

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;T;T;.;T;T;T;.

Eigen

Benign

0.010

Eigen_PC

Benign

0.034

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.81

T;T;.;T;T;T;T;T

MetaRNN

Benign

0.011

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;.;L;.;.;.;.;.

PhyloP100

2.8

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.6

.;D;N;.;.;.;.;.

REVEL

Benign

0.078

Sift

Uncertain

0.015

.;D;T;.;.;.;.;.

Sift4G

Benign

0.10

T;T;T;T;T;T;T;T

Polyphen

0.98

D;.;D;.;.;.;.;.

Vest4

0.26

MVP

0.25

MPC

0.32

ClinPred

0.045

GERP RS

4.2

Varity_R

0.13

gMVP

0.50

Mutation Taster

=89/11

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over