rs61756235

Variant names:

• chr6-137876122-G-A
• rs61756235
• NM_001270508.2:c.761G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001270508.2(TNFAIP3):​c.761G>A​(p.Ser254Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S254I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TNFAIP3 NM_001270508.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.08
• 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: 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1697312).
• BS2: High AC in GnomAdExome4 at 7 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.761G>A	p.Ser254Asn	missense	Exon 5 of 9	NP_001257437.1	P21580
	TNFAIP3	NM_001270507.2		c.761G>A	p.Ser254Asn	missense	Exon 5 of 9	NP_001257436.1	P21580
	TNFAIP3	NM_006290.4		c.761G>A	p.Ser254Asn	missense	Exon 5 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.761G>A	p.Ser254Asn	missense	Exon 5 of 9	ENSP00000481570.1	P21580
	TNFAIP3	ENST00000237289.8	TSL:1	c.761G>A	p.Ser254Asn	missense	Exon 5 of 9	ENSP00000237289.4	P21580
	TNFAIP3	ENST00000420009.6	TSL:3	c.761G>A	p.Ser254Asn	missense	Exon 5 of 9	ENSP00000401562.2	P21580

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461772 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727180

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111956

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.056
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.95	L
PhyloP100		4.1
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.056
Sift	Benign	0.14	T
Sift4G	Benign	0.24	T
Polyphen		0.0070	B
Vest4		0.33
MutPred		0.49		Loss of sheet (P = 0.1398)
MVP		0.24
MPC		0.28
ClinPred		0.58	D
GERP RS		4.7
Varity_R		0.20
gMVP		0.56
Mutation Taster		=78/22	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: rs61756235; hg19: chr6-138197259; COSMIC: COSV52798522; COSMIC: COSV52798522;