rs719149

Variant names:

• chr6-137871608-G-A
• rs719149
• NM_001270508.2:c.295+86G>A

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.295+86G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,452,064 control chromosomes in the GnomAD database, including 12,996 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (4769 hom., cov: 32)
  • Exomes 𝑓: 0.095 (8227 hom.)
• Consequence: TNFAIP3 NM_001270508.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.140
• Publications: 16 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 (BayesDel_noAF=-0.84).
• BP6: Variant 6-137871608-G-A is Benign according to our data. Variant chr6-137871608-G-A is described in ClinVar as Benign. ClinVar VariationId is 1221925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFAIP3	NM_001270508.2	c.295+86G>A		intron_variant	Intron 2 of 8	ENST00000612899.5	NP_001257437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFAIP3	ENST00000612899.5	c.295+86G>A		intron_variant	Intron 2 of 8	5	NM_001270508.2	ENSP00000481570.1

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28529 AN: 152038 Hom.: 4749 Cov.: 32

Gnomad AFR AF: 0.452

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.0548

Gnomad SAS AF: 0.0978

Gnomad FIN AF: 0.0254

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.0801

Gnomad OTH AF: 0.168

GnomAD4 exome AF: 0.0945 AC: 122853 AN: 1299908 Hom.: 8227 AF XY: 0.0938 AC XY: 60390 AN XY: 643650

African (AFR) AF: 0.463 AC: 13634 AN: 29438

American (AMR) AF: 0.138 AC: 4425 AN: 32054

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 2559 AN: 20656

East Asian (EAS) AF: 0.0711 AC: 2750 AN: 38672

South Asian (SAS) AF: 0.102 AC: 7244 AN: 70698

European-Finnish (FIN) AF: 0.0278 AC: 1242 AN: 44698

Middle Eastern (MID) AF: 0.139 AC: 517 AN: 3724

European-Non Finnish (NFE) AF: 0.0837 AC: 84159 AN: 1005546

Other (OTH) AF: 0.116 AC: 6323 AN: 54422

GnomAD4 genome AF: 0.188 AC: 28593 AN: 152156 Hom.: 4769 Cov.: 32 AF XY: 0.183 AC XY: 13586 AN XY: 74422

African (AFR) AF: 0.453 AC: 18758 AN: 41438

American (AMR) AF: 0.161 AC: 2464 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 425 AN: 3468

East Asian (EAS) AF: 0.0551 AC: 286 AN: 5186

South Asian (SAS) AF: 0.0970 AC: 469 AN: 4834

European-Finnish (FIN) AF: 0.0254 AC: 269 AN: 10610

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.0801 AC: 5447 AN: 68004

Other (OTH) AF: 0.169 AC: 356 AN: 2112

Alfa AF: 0.158 Hom.: 872

Bravo AF: 0.208

Asia WGS AF: 0.0980 AC: 341 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 27% of patients studied by a panel of primary immunodeficiencies. Number of patients: 26. Only high quality variants are reported. -

not provided Benign:1

May 16, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.7
DANN	Benign	0.67
PhyloP100		0.14
Mutation Taster		=100/0	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: rs719149; hg19: chr6-138192745; COSMIC: COSV104584204;