rs376205580

chr6-137874871-A-Gchr6-137874871-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001270508.2(TNFAIP3):c.322A>G(p.Thr108Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,613,970 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00041 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (6 hom.)
• Consequence: TNFAIP3 NM_001270508.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 1.41

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020262599).
• BP6: Variant 6-137874871-A-G is Benign according to our data. Variant chr6-137874871-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 135331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-137874871-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000407 (62/152222) while in subpopulation AMR AF= 0.00222 (34/15286). AF 95% confidence interval is 0.00164. There are 6 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 53 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFAIP3	NM_001270508.2	c.322A>G	p.Thr108Ala	missense_variant	3/9	ENST00000612899.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFAIP3	ENST00000612899.5	c.322A>G	p.Thr108Ala	missense_variant	3/9	5	NM_001270508.2	P1

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152104 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000116 AC: 29 AN: 250840 Hom.: 0 AF XY: 0.0000812 AC XY: 11 AN XY: 135504

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000761

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000101 AC: 148 AN: 1461748 Hom.: 6 Cov.: 33 AF XY: 0.0000949 AC XY: 69 AN XY: 727170

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000428

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00190

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152222 Hom.: 6 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74394

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000212

ExAC AF: 0.000157 AC: 19

Asia WGS AF: 0.0380 AC: 130 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	TNFAIP3: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Autoinflammatory syndrome, familial, Behcet-like 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 03, 2023

- -

A20 haploinsufficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Jul 30, 2019

- -

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	0.054
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	1.6
Dann	Benign	0.49
DEOGEN2	Benign	0.10	T;T;T;.;T;T;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.71	T;T;.;T;T;T;T;T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.020	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.2	N;.;N;.;.;.;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;B;.;.;.;.;.
Vest4		0.24
MutPred		0.60		Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);
MVP		0.25
MPC		0.30
ClinPred		0.0066	T
GERP RS		-0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.24

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

Other links and lift over

dbSNP: rs376205580; hg19: chr6-138196008; COSMIC: COSV52799446; COSMIC: COSV52799446;