6-137871292-G-A

Position:

chr6-137871292-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BP4

The NM_001270508.2(TNFAIP3):c.65G>A(p.Arg22Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Consequence

TNFAIP3
NM_001270508.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.22

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_addAF, Cadd, Dann, Eigen, FATHMM_MKL, phyloP100way_vertebrate [when max_spliceai, M_CAP, MetaRNN, MutationTaster, REVEL was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.38946503).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFAIP3	NM_001270508.2 linkuse as main transcript	c.65G>A	p.Arg22Gln	missense_variant	2/9	ENST00000612899.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFAIP3	ENST00000612899.5 linkuse as main transcript	c.65G>A	p.Arg22Gln	missense_variant	2/9	5	NM_001270508.2	P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251346

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 21, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with chronic urticaria and angioedema (PMID: 29682366). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 22 of the TNFAIP3 protein (p.Arg22Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.50

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

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

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

M_CAP

Benign

0.021

MetaRNN

Benign

0.39

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

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

M;.;.;M;.;.;.;.;.;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-4.0

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

REVEL

Benign

0.23

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

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

Vest4

0.77

MVP

0.62

MPC

1.1

ClinPred

1.0

GERP RS

6.0

Varity_R

0.61

gMVP

0.74

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