NM_001270508.2:c.380T>G

Variant names:

• chr6-137874929-T-G
• rs2230926
• NM_001270508.2:c.380T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001270508.2(TNFAIP3):​c.380T>G​(p.Phe127Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0504 in 1,614,106 control chromosomes in the GnomAD database, including 6,197 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (2847 hom., cov: 32)
  • Exomes 𝑓: 0.043 (3350 hom.)
• Consequence: TNFAIP3 NM_001270508.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 1.33
• Publications: 252 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011356473).
• BP6: Variant 6-137874929-T-G is Benign according to our data. Variant chr6-137874929-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270508.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFAIP3	NM_001270508.2	MANE Select	c.380T>G	p.Phe127Cys	missense	Exon 3 of 9	NP_001257437.1
	TNFAIP3	NM_001270507.2		c.380T>G	p.Phe127Cys	missense	Exon 3 of 9	NP_001257436.1
	TNFAIP3	NM_006290.4		c.380T>G	p.Phe127Cys	missense	Exon 3 of 9	NP_006281.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFAIP3	ENST00000612899.5	TSL:5 MANE Select	c.380T>G	p.Phe127Cys	missense	Exon 3 of 9	ENSP00000481570.1
	TNFAIP3	ENST00000237289.8	TSL:1	c.380T>G	p.Phe127Cys	missense	Exon 3 of 9	ENSP00000237289.4
	TNFAIP3	ENST00000420009.6	TSL:3	c.380T>G	p.Phe127Cys	missense	Exon 3 of 9	ENSP00000401562.2

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19203 AN: 152110 Hom.: 2837 Cov.: 32

Gnomad AFR AF: 0.363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0732

Gnomad ASJ AF: 0.0441

Gnomad EAS AF: 0.0425

Gnomad SAS AF: 0.0316

Gnomad FIN AF: 0.0168

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0313

Gnomad OTH AF: 0.110

GnomAD2 exomes AF: 0.0542 AC: 13619 AN: 251476 AF XY: 0.0480

Gnomad AFR exome AF: 0.364

Gnomad AMR exome AF: 0.0356

Gnomad ASJ exome AF: 0.0516

Gnomad EAS exome AF: 0.0370

Gnomad FIN exome AF: 0.0148

Gnomad NFE exome AF: 0.0329

Gnomad OTH exome AF: 0.0454

GnomAD4 exome AF: 0.0425 AC: 62168 AN: 1461878 Hom.: 3350 Cov.: 33 AF XY: 0.0412 AC XY: 29941 AN XY: 727240

African (AFR) AF: 0.367 AC: 12294 AN: 33478

American (AMR) AF: 0.0395 AC: 1765 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0473 AC: 1235 AN: 26136

East Asian (EAS) AF: 0.0582 AC: 2310 AN: 39696

South Asian (SAS) AF: 0.0309 AC: 2666 AN: 86258

European-Finnish (FIN) AF: 0.0161 AC: 858 AN: 53420

Middle Eastern (MID) AF: 0.0569 AC: 328 AN: 5768

European-Non Finnish (NFE) AF: 0.0333 AC: 37065 AN: 1112004

Other (OTH) AF: 0.0604 AC: 3647 AN: 60394

GnomAD4 genome AF: 0.126 AC: 19251 AN: 152228 Hom.: 2847 Cov.: 32 AF XY: 0.123 AC XY: 9121 AN XY: 74450

African (AFR) AF: 0.363 AC: 15049 AN: 41480

American (AMR) AF: 0.0731 AC: 1119 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0441 AC: 153 AN: 3472

East Asian (EAS) AF: 0.0430 AC: 223 AN: 5186

South Asian (SAS) AF: 0.0313 AC: 151 AN: 4832

European-Finnish (FIN) AF: 0.0168 AC: 178 AN: 10616

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0313 AC: 2129 AN: 68026

Other (OTH) AF: 0.110 AC: 232 AN: 2112

Alfa AF: 0.0631 Hom.: 4332

Bravo AF: 0.140

TwinsUK AF: 0.0348 AC: 129

ALSPAC AF: 0.0332 AC: 128

ESP6500AA AF: 0.356 AC: 1570

ESP6500EA AF: 0.0321 AC: 276

ExAC AF: 0.0613 AC: 7438

Asia WGS AF: 0.0510 AC: 180 AN: 3478

EpiCase AF: 0.0346

EpiControl AF: 0.0346

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 30, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31131138, 30529365, 26338037, 26502338, 19165918, 24023622, 24728327, 20169177, 19838193, 19165919, 19774492, 20617138, 20483768, 22924496, 21326317, 24159176, 20112363, 23261300)

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

Nov 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Benign	0.89
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Benign	0.022
Sift	Benign	0.22	T
Sift4G	Benign	0.11	T
Polyphen		0.0080	B
Vest4		0.14
MPC		0.49
ClinPred		0.039	T
GERP RS		-0.057
Varity_R		0.46
gMVP		0.55
Mutation Taster		=89/11	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2230926; hg19: chr6-138196066; COSMIC: COSV52797460; COSMIC: COSV52797460;