rs5029947

chr6-137875680-C-Gchr6-137875680-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001270508.2(TNFAIP3):c.487-8C>G variant causes a splice region, splice polypyrimidine tract, 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_001270508.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.002719
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.378

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2249 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFAIP3	NM_001270508.2	c.487-8C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000612899.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFAIP3	ENST00000612899.5	c.487-8C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001270508.2	P1

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

GnomAD3 exomes AF: 0.00511 AC: 1282 AN: 250862 Hom.: 19 AF XY: 0.00402 AC XY: 545 AN XY: 135582

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 SAS exome AF: 0.000131

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

Gnomad4 AFR exome AF: 0.0476

Gnomad4 AMR exome AF: 0.00886

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00157

Gnomad4 OTH exome AF: 0.00721

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

Gnomad4 AFR AF: 0.0459

Gnomad4 AMR AF: 0.0138

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00149

Gnomad4 OTH AF: 0.0133

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autoinflammatory syndrome, familial, Behcet-like 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 03, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	1.4
Dann	Benign	0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs5029947; hg19: chr6-138196817; COSMIC: COSV104584289; COSMIC: COSV104584289;