rs142752989

Variant names:

• chr6-137879079-C-T
• rs142752989
• NM_001270508.2:c.1634C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001270508.2(TNFAIP3):​c.1634C>T​(p.Ala545Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000906 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00094 (0 hom.)
• Consequence: TNFAIP3 NM_001270508.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3 O:1
• Conservation: PhyloP100: 2.62
• Publications: 9 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03883007).
• BP6: Variant 6-137879079-C-T is Benign according to our data. Variant chr6-137879079-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135338.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000631 (96/152208) while in subpopulation NFE AF = 0.00119 (81/68030). AF 95% confidence interval is 0.000981. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 96 AD,Unknown 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.1634C>T	p.Ala545Val	missense	Exon 7 of 9	NP_001257437.1	P21580
	TNFAIP3	NM_001270507.2		c.1634C>T	p.Ala545Val	missense	Exon 7 of 9	NP_001257436.1	P21580
	TNFAIP3	NM_006290.4		c.1634C>T	p.Ala545Val	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.1634C>T	p.Ala545Val	missense	Exon 7 of 9	ENSP00000481570.1	P21580
	TNFAIP3	ENST00000237289.8	TSL:1	c.1634C>T	p.Ala545Val	missense	Exon 7 of 9	ENSP00000237289.4	P21580
	TNFAIP3	ENST00000420009.6	TSL:3	c.1634C>T	p.Ala545Val	missense	Exon 7 of 9	ENSP00000401562.2	P21580

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000453 AC: 114 AN: 251460 AF XY: 0.000397

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000897

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.000935 AC: 1367 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.000936 AC XY: 681 AN XY: 727242

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44722

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

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

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53412

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

European-Non Finnish (NFE) AF: 0.00119 AC: 1319 AN: 1112010

Other (OTH) AF: 0.000397 AC: 24 AN: 60396

GnomAD4 genome AF: 0.000631 AC: 96 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.000484 AC XY: 36 AN XY: 74364

African (AFR) AF: 0.000289 AC: 12 AN: 41452

American (AMR) AF: 0.000131 AC: 2 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00119 AC: 81 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00118 Hom.: 0

Bravo AF: 0.000695

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000453 AC: 55

EpiCase AF: 0.000709

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	1	-	Autoinflammatory syndrome, familial, Behcet-like (1)
-	-	1	not specified (2)
-	1	-	TNFAIP3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	16
DANN	Benign	0.90
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.6
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.083
Sift	Benign	0.66	T
Sift4G	Benign	0.27	T
Polyphen		0.041	B
Vest4		0.37
MVP		0.31
MPC		0.36
ClinPred		0.019	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.073
gMVP		0.54
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs142752989; hg19: chr6-138200216; COSMIC: COSV105103554;