chr6-137871187-C-CT

Variant names:

• chr6-137871187-C-CT
• rs3214646
• NM_001270508.2:c.-15-15dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001270508.2(TNFAIP3):​c.-15-15dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,077,466 control chromosomes in the GnomAD database, including 2 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0011 (2 hom., cov: 32)
  • Exomes 𝑓: 0.014 (0 hom.)
• Consequence: TNFAIP3 NM_001270508.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0520
• Publications: 2 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00112 (165/146674) while in subpopulation SAS AF = 0.0123 (57/4622). AF 95% confidence interval is 0.00977. There are 2 homozygotes in GnomAd4. There are 94 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 165 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFAIP3	NM_001270508.2	c.-15-15dupT		intron_variant	Intron 1 of 8	ENST00000612899.5	NP_001257437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFAIP3	ENST00000612899.5	c.-15-26_-15-25insT		intron_variant	Intron 1 of 8	5	NM_001270508.2	ENSP00000481570.1

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 165 AN: 146600 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000576

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000272

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00314

Gnomad SAS AF: 0.0125

Gnomad FIN AF: 0.000318

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000922

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0267 AC: 1652 AN: 61868 AF XY: 0.0282

Gnomad AFR exome AF: 0.0144

Gnomad AMR exome AF: 0.0256

Gnomad ASJ exome AF: 0.0412

Gnomad EAS exome AF: 0.0263

Gnomad FIN exome AF: 0.0288

Gnomad NFE exome AF: 0.0201

Gnomad OTH exome AF: 0.0298

GnomAD4 exome AF: 0.0135 AC: 12568 AN: 930792 Hom.: 0 Cov.: 18 AF XY: 0.0134 AC XY: 6228 AN XY: 463078

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0116 AC: 238 AN: 20594

American (AMR) AF: 0.00878 AC: 214 AN: 24372

Ashkenazi Jewish (ASJ) AF: 0.0113 AC: 179 AN: 15810

East Asian (EAS) AF: 0.0116 AC: 313 AN: 26868

South Asian (SAS) AF: 0.0261 AC: 1368 AN: 52404

European-Finnish (FIN) AF: 0.00958 AC: 339 AN: 35390

Middle Eastern (MID) AF: 0.00830 AC: 34 AN: 4098

European-Non Finnish (NFE) AF: 0.0132 AC: 9380 AN: 713046

Other (OTH) AF: 0.0132 AC: 503 AN: 38210

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00112 AC: 165 AN: 146674 Hom.: 2 Cov.: 32 AF XY: 0.00132 AC XY: 94 AN XY: 71410

African (AFR) AF: 0.000599 AC: 24 AN: 40058

American (AMR) AF: 0.000272 AC: 4 AN: 14706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3406

East Asian (EAS) AF: 0.00315 AC: 16 AN: 5078

South Asian (SAS) AF: 0.0123 AC: 57 AN: 4622

European-Finnish (FIN) AF: 0.000318 AC: 3 AN: 9430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.000922 AC: 61 AN: 66178

Other (OTH) AF: 0.00 AC: 0 AN: 2016

Alfa AF: 0.0116 Hom.: 5

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.052
Mutation Taster		=100/0	polymorphism

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: rs3214646; hg19: chr6-138192324;