rs142253225

Positions:

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:

TNFAIP3 (HGNC:):

TNFAIP3 links:

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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, Uncertain_significance=2, not_provided=1, Benign=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/exons	MANE	Protein	UniProt
TNFAIP3	NM_001270508.2 linkuse as main transcript	c.1939A>C	p.Thr647Pro	missense_variant	8/9	ENST00000612899.5	NP_001257437.1	P21580

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFAIP3	ENST00000612899.5 linkuse as main transcript	c.1939A>C	p.Thr647Pro	missense_variant	8/9	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

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	TNFAIP3: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Autoinflammatory syndrome, familial, Behcet-like

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 16, 2021	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 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% (511/282864 alleles) in the Genome Aggregation Database. The threonine at codon 647 is weakly conserved, and 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Oct 04, 2020	- -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

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