rs150355046

Variant names:

• chr6-137881177-G-A
• rs150355046
• NM_001270508.2:c.2231G>A
• TNFAIP3 p.Gly744Asp

Your query was ambiguous. Multiple possible variants found:

• chr6-137881177-G-A
• chr6-137881177-G-C

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.2231G>A​(p.Gly744Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000618 in 1,613,616 control chromosomes in the GnomAD database, including 1 homozygotes. 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). Synonymous variant affecting the same amino acid position (i.e. G744G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00064 (1 hom.)
• Consequence: TNFAIP3 NM_001270508.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6 O:1
• Conservation: PhyloP100: 0.781
• Publications: 10 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), PanelApp Australia
• 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

ENSG00000287393 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.029620975).
• BP6: Variant 6-137881177-G-A is Benign according to our data. Variant chr6-137881177-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135348.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000388 (59/151974) while in subpopulation NFE AF = 0.000647 (44/68006). AF 95% confidence interval is 0.000495. There are 0 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 59 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.2231G>A	p.Gly744Asp	missense	Exon 9 of 9	NP_001257437.1	P21580
	TNFAIP3	NM_001270507.2		c.2231G>A	p.Gly744Asp	missense	Exon 9 of 9	NP_001257436.1	P21580
	TNFAIP3	NM_006290.4		c.2231G>A	p.Gly744Asp	missense	Exon 9 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.2231G>A	p.Gly744Asp	missense	Exon 9 of 9	ENSP00000481570.1	P21580
	TNFAIP3	ENST00000237289.8	TSL:1	c.2231G>A	p.Gly744Asp	missense	Exon 9 of 9	ENSP00000237289.4	P21580
	TNFAIP3	ENST00000420009.6	TSL:3	c.2231G>A	p.Gly744Asp	missense	Exon 9 of 9	ENSP00000401562.2	P21580

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 151974 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.000481

GnomAD2 exomes AF: 0.000459 AC: 115 AN: 250718 AF XY: 0.000479

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000740

Gnomad NFE exome AF: 0.000724

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000642 AC: 939 AN: 1461642 Hom.: 1 Cov.: 31 AF XY: 0.000611 AC XY: 444 AN XY: 727126

African (AFR) AF: 0.000239 AC: 8 AN: 33476

American (AMR) AF: 0.000134 AC: 6 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.000582 AC: 31 AN: 53246

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

European-Non Finnish (NFE) AF: 0.000781 AC: 868 AN: 1111982

Other (OTH) AF: 0.000414 AC: 25 AN: 60396

GnomAD4 genome AF: 0.000388 AC: 59 AN: 151974 Hom.: 0 Cov.: 32 AF XY: 0.000404 AC XY: 30 AN XY: 74206

African (AFR) AF: 0.000145 AC: 6 AN: 41364

American (AMR) AF: 0.000262 AC: 4 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68006

Other (OTH) AF: 0.000481 AC: 1 AN: 2078

Alfa AF: 0.000597 Hom.: 0

Bravo AF: 0.000363

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	not provided (6)
-	1	-	Autoinflammatory syndrome, familial, Behcet-like 1 (1)
-	-	1	TNFAIP3-related disorder (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	2.5
DANN	Benign	0.80
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.78
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.30	N
REVEL	Benign	0.023
Sift	Benign	0.49	T
Sift4G	Benign	0.52	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.51
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs150355046;

hg19: chr6-138202314;

COSMIC: COSV104584251;