Genetic Variant TNFAIP3:p.Gly744Ala (chr6-137881177-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001270508.2(TNFAIP3):c.2231G>C(p.Gly744Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G744D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TNFAIP3
NM_001270508.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.781

Publications

0 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:

ENSG00000287393 (HGNC:):

ENSG00000287393 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.062456906).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFAIP3	NM_001270508.2 link	c.2231G>C	p.Gly744Ala	missense_variant	Exon 9 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.2231G>C	p.Gly744Ala	missense_variant	Exon 9 of 9	5	NM_001270508.2	ENSP00000481570.1		P21580

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461642

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53246

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111982

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.84

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.22

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.39

T;.

M_CAP

Benign

0.0055

MetaRNN

Benign

0.062

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.0

L;L

PhyloP100

0.78

PrimateAI

Benign

0.32

PROVEAN

Benign

0.14

.;N

REVEL

Benign

0.013

Sift

Benign

0.64

.;T

Sift4G

Benign

0.55

T;T

Polyphen

0.0

B;B

Vest4

0.080

MutPred

0.17

Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);

MVP

0.26

MPC

0.32

ClinPred

0.054

GERP RS

-1.1

Varity_R

0.034

gMVP

0.41

Mutation Taster

=98/2

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over