rs587778712

Variant names:

• chr6-137879096-C-T
• rs587778712
• NM_001270508.2:c.1651C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001270508.2(TNFAIP3):​c.1651C>T​(p.Leu551Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,461,878 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (1 hom.)
• Consequence: TNFAIP3 NM_001270508.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 0.397
• Publications: 1 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: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hereditary pediatric Behçet-like disease

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000287393 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.061516374).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000226 (33/1461878) while in subpopulation SAS AF = 0.000371 (32/86256). AF 95% confidence interval is 0.00027. There are 1 homozygotes in GnomAdExome4. There are 21 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 33 Unknown,AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFAIP3	NM_001270508.2	MANE Select	c.1651C>T	p.Leu551Phe	missense	Exon 7 of 9	NP_001257437.1	P21580
	TNFAIP3	NM_001270507.2		c.1651C>T	p.Leu551Phe	missense	Exon 7 of 9	NP_001257436.1	P21580
	TNFAIP3	NM_006290.4		c.1651C>T	p.Leu551Phe	missense	Exon 7 of 9	NP_006281.1	P21580

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFAIP3	ENST00000612899.5	TSL:5 MANE Select	c.1651C>T	p.Leu551Phe	missense	Exon 7 of 9	ENSP00000481570.1	P21580
	TNFAIP3	ENST00000237289.8	TSL:1	c.1651C>T	p.Leu551Phe	missense	Exon 7 of 9	ENSP00000237289.4	P21580
	TNFAIP3	ENST00000420009.6	TSL:3	c.1651C>T	p.Leu551Phe	missense	Exon 7 of 9	ENSP00000401562.2	P21580

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251458 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461878 Hom.: 1 Cov.: 31 AF XY: 0.0000289 AC XY: 21 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000371 AC: 32 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.40
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.023
Sift	Benign	0.12	T
Sift4G	Benign	0.13	T
Polyphen		0.0020	B
Vest4		0.12
MutPred		0.14		Gain of sheet (P = 0.0344)
MVP		0.16
MPC		0.33
ClinPred		0.040	T
GERP RS		-4.4
Varity_R		0.075
gMVP		0.45
Mutation Taster		=95/5	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: rs587778712; hg19: chr6-138200233;