rs5029941

Positions:

chr6-137874923-C-T

Variant summary

Our verdict is Benign. Variant got -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. 12/20 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

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:

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=0.010955274).

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 id is 135332.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, not_provided=1, Benign=1}.

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 805 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFAIP3	NM_001270508.2 linkuse as main transcript	c.374C>T	p.Ala125Val	missense_variant	3/9	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.374C>T	p.Ala125Val	missense_variant	3/9	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

GnomAD3 exomes

AF:

0.00120

AC:

303

AN:

251472

Hom.:

AF XY:

0.000876

AC XY:

119

AN XY:

135906

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 SAS exome

AF:

0.0000327

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

Gnomad4 AFR exome

AF:

0.0173

Gnomad4 AMR exome

AF:

0.000693

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.00101

GnomAD4 genome

AF:

0.00528

AC:

805

AN:

152330

Hom.:

Cov.:

AF XY:

0.00510

AC XY:

380

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0184

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00112

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

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 13, 2015	- -

Autoinflammatory syndrome, familial, Behcet-like

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 18, 2021

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. 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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

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

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;.;.;.;.;.

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

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

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