rs142253225

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001270508.2(TNFAIP3):c.1939A>C(p.Thr647Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,614,182 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 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 0.0019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 2 hom. )

Consequence

TNFAIP3
NM_001270508.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4O:1

Conservation

PhyloP100: -0.431

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005445957).

BP6

Variant 6-137880103-A-C is Benign according to our data. Variant chr6-137880103-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135345.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=2, not_provided=1}. Variant chr6-137880103-A-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00193 (294/152288) while in subpopulation AMR AF= 0.00497 (76/15286). AF 95% confidence interval is 0.00407. There are 0 homozygotes in gnomad4. There are 146 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 294 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFAIP3	NM_001270508.2 link	c.1939A>C	p.Thr647Pro	missense_variant	Exon 8 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.1939A>C	p.Thr647Pro	missense_variant	Exon 8 of 9	5	NM_001270508.2	ENSP00000481570.1		P21580

Frequencies

GnomAD3 genomes

AF:

0.00193

AC:

294

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00498

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00221

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00188

AC:

474

AN:

251476

Hom.:

AF XY:

0.00196

AC XY:

267

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00275

Gnomad ASJ exome

AF:

0.00556

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000751

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00238

Gnomad OTH exome

AF:

0.00293

GnomAD4 exome

AF:

0.00200

AC:

2923

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00204

AC XY:

1482

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.00282

Gnomad4 ASJ exome

AF:

0.00608

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000684

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.00209

Gnomad4 OTH exome

AF:

0.00235

GnomAD4 genome

AF:

0.00193

AC:

294

AN:

152288

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

146

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000601

Gnomad4 AMR

AF:

0.00497

Gnomad4 ASJ

AF:

0.00720

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00221

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00221

Hom.:

Bravo

AF:

0.00213

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00188

AC:

228

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00273

EpiControl

AF:

0.00379

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TNFAIP3: BP4, BS1, BS2 -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Autoinflammatory syndrome, familial, Behcet-like

Uncertain:1

Oct 04, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autoinflammatory syndrome, familial, Behcet-like 1

Uncertain:1

Nov 12, 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.1939A>C; p.Thr647Pro variant (rs142253225) is reported in the literature in one individual with periodic fever and autoinflammatory disease and in a family with symptoms similar to familial Behcet-like autoinflammatory syndrome (Fathalla 2021, Mulhern 2019). This variant has also been found in patients with autoinflammatory conditions (El Naofal 2023, Liu 2017). This variant is also reported in ClinVar (Variation ID: 135345). Functional analyses of the variant protein in heterologous cells showed reduced expression and lack of significant suppression of the NF-kB signaling pathway (Kadowaki 2021). However, this variant is found in the general population with an allele frequency of 0.18% (511/282,864 alleles) in the Genome Aggregation Database(v2.1.1). Computational analyses predict that this variant is neutral (REVEL: 0.027). Due to conflicting information, the clinical significance of the p.Thr647Pro variant is uncertain at this time. References: El Naofal M et al. The genomic landscape of rare disorders in the Middle East. Genome Med. 2023 Jan 27;15(1):5. PMID: 36703223. Liu Y et al. Genetic and Functional Associations with Decreased Anti-inflammatory Tumor Necrosis Factor Alpha Induced Protein 3 in Macrophages from Subjects with Axial Spondyloarthritis. Front Immunol. 2017 Jul 24;8:860. PMID: 28791018. Mulhern CM et al. Janus kinase 1/2 inhibition for the treatment of autoinflammation associated with heterozygous TNFAIP3 mutation. J Allergy Clin Immunol. 2019 Sep;144(3):863-866.e5. PMID: 31175876. Fathalla BM et al. The genomic landscape of pediatric rheumatology disorders in the Middle East. Hum Mutat. 2021 Apr;42(4):e1-e14. PMID: 33440462. Kadowaki S et al. Functional analysis of novel A20 variants in patients with atypical inflammatory diseases. Arthritis Res Ther. 2021 Feb 6;23(1):52. PMID: 33549127. -

not specified

Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.65

CADD

Benign

8.9

DANN

Benign

0.96

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.25

M_CAP

Benign

0.0031

MetaRNN

Benign

0.0054

MetaSVM

Benign

-0.99

Sift4G

Benign

0.16

Vest4

0.35

MVP

0.37

ClinPred

0.0027

GERP RS

-2.6

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over