6-137877081-C-G

Variant names:

• chr6-137877081-C-G
• rs864321626
• NM_001270508.2:c.811C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001270508.2(TNFAIP3):​c.811C>G​(p.Arg271Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000698 in 1,433,252 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R271Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TNFAIP3 NM_001270508.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.46
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.811C>G	p.Arg271Gly	missense	Exon 6 of 9	NP_001257437.1	P21580
	TNFAIP3	NM_001270507.2		c.811C>G	p.Arg271Gly	missense	Exon 6 of 9	NP_001257436.1	P21580
	TNFAIP3	NM_006290.4		c.811C>G	p.Arg271Gly	missense	Exon 6 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.811C>G	p.Arg271Gly	missense	Exon 6 of 9	ENSP00000481570.1	P21580
	TNFAIP3	ENST00000237289.8	TSL:1	c.811C>G	p.Arg271Gly	missense	Exon 6 of 9	ENSP00000237289.4	P21580
	TNFAIP3	ENST00000420009.6	TSL:3	c.811C>G	p.Arg271Gly	missense	Exon 6 of 9	ENSP00000401562.2	P21580

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1433252 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 711130

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

African (AFR) AF: 0.00 AC: 0 AN: 32110

American (AMR) AF: 0.00 AC: 0 AN: 39998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39020

South Asian (SAS) AF: 0.00 AC: 0 AN: 82408

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5634

European-Non Finnish (NFE) AF: 9.12e-7 AC: 1 AN: 1097078

Other (OTH) AF: 0.00 AC: 0 AN: 59124

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.5
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.22
Sift	Benign	0.031	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.43		Gain of sheet (P = 0.0221)
MVP		0.65
MPC		1.2
ClinPred		0.89	D
GERP RS		4.1
Varity_R		0.76
gMVP		0.86
Mutation Taster		=35/65	disease causing

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: rs864321626; hg19: chr6-138198218;