rs5029947

Variant names:

• chr6-137875680-C-G
• rs5029947
• NM_001270508.2:c.487-8C>G

Your query was ambiguous. Multiple possible variants found:

• chr6-137875680-C-G
• chr6-137875680-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006290.4(TNFAIP3):​c.487-8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00405 in 1,613,456 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (38 hom., cov: 33)
  • Exomes 𝑓: 0.0029 (57 hom.)
• Consequence: TNFAIP3 NM_006290.4 splice_region, intron
• Scores: Splicing: ADA: 0.002719
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.378
• 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)
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 6-137875680-C-G is Benign according to our data. Variant chr6-137875680-C-G is described in ClinVar as Benign. ClinVar VariationId is 769695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0148 (2254/152176) while in subpopulation AFR AF = 0.0459 (1906/41496). AF 95% confidence interval is 0.0442. There are 38 homozygotes in GnomAd4. There are 1056 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2254 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006290.4. 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.487-8C>G		splice_region intron	N/A	NP_001257437.1
	TNFAIP3	NM_001270507.2		c.487-8C>G		splice_region intron	N/A	NP_001257436.1
	TNFAIP3	NM_006290.4		c.487-8C>G		splice_region intron	N/A	NP_006281.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFAIP3	ENST00000612899.5	TSL:5 MANE Select	c.487-8C>G		splice_region intron	N/A	ENSP00000481570.1
	TNFAIP3	ENST00000237289.8	TSL:1	c.487-8C>G		splice_region intron	N/A	ENSP00000237289.4
	TNFAIP3	ENST00000420009.6	TSL:3	c.487-8C>G		splice_region intron	N/A	ENSP00000401562.2

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2249 AN: 152058 Hom.: 37 Cov.: 33

Gnomad AFR AF: 0.0459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0138

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00149

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00511 AC: 1282 AN: 250862 AF XY: 0.00402

Gnomad AFR exome AF: 0.0479

Gnomad AMR exome AF: 0.00766

Gnomad ASJ exome AF: 0.000696

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00159

Gnomad OTH exome AF: 0.00734

GnomAD4 exome AF: 0.00293 AC: 4275 AN: 1461280 Hom.: 57 Cov.: 32 AF XY: 0.00272 AC XY: 1978 AN XY: 726944

African (AFR) AF: 0.0476 AC: 1591 AN: 33444

American (AMR) AF: 0.00886 AC: 395 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86134

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53406

Middle Eastern (MID) AF: 0.0113 AC: 65 AN: 5760

European-Non Finnish (NFE) AF: 0.00157 AC: 1751 AN: 1111768

Other (OTH) AF: 0.00721 AC: 435 AN: 60358

GnomAD4 genome AF: 0.0148 AC: 2254 AN: 152176 Hom.: 38 Cov.: 33 AF XY: 0.0142 AC XY: 1056 AN XY: 74408

African (AFR) AF: 0.0459 AC: 1906 AN: 41496

American (AMR) AF: 0.0138 AC: 211 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10590

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00149 AC: 101 AN: 67998

Other (OTH) AF: 0.0133 AC: 28 AN: 2112

Alfa AF: 0.00534 Hom.: 3

Bravo AF: 0.0178

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00235

EpiControl AF: 0.00237

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autoinflammatory syndrome, familial, Behcet-like 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.4
DANN	Benign	0.69
PhyloP100		-0.38
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0027
dbscSNV1_RF	Benign	0.058
SpliceAI score (max)		0.020		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: rs5029947; hg19: chr6-138196817; COSMIC: COSV104584289;