rs146534657

Positions:

• chr6-137874854-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001270508.2(TNFAIP3):​c.305A>G​(p.Asn102Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00448 in 1,613,286 control chromosomes in the GnomAD database, including 172 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (23 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (149 hom.)
• Consequence: TNFAIP3 NM_001270508.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 8.34

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 (MetaRNN=0.015530705).
• BP6: Variant 6-137874854-A-G is Benign according to our data. Variant chr6-137874854-A-G is described in ClinVar as [Benign]. Clinvar id is 135330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0595 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFAIP3	NM_001270508.2	c.305A>G	p.Asn102Ser	missense_variant	3/9	ENST00000612899.5	NP_001257437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFAIP3	ENST00000612899.5	c.305A>G	p.Asn102Ser	missense_variant	3/9	5	NM_001270508.2	ENSP00000481570	P1

Frequencies

GnomAD3 genomes AF: 0.00653 AC: 993 AN: 152124 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.000773

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0453

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0127

Gnomad SAS AF: 0.0265

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.0135 AC: 3388 AN: 250422 Hom.: 97 AF XY: 0.0123 AC XY: 1665 AN XY: 135268

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0642

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0140

Gnomad SAS exome AF: 0.0248

Gnomad FIN exome AF: 0.00213

Gnomad NFE exome AF: 0.000575

Gnomad OTH exome AF: 0.00703

GnomAD4 exome AF: 0.00426 AC: 6229 AN: 1461044 Hom.: 149 Cov.: 33 AF XY: 0.00469 AC XY: 3405 AN XY: 726706

Gnomad4 AFR exome AF: 0.000479

Gnomad4 AMR exome AF: 0.0614

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0124

Gnomad4 SAS exome AF: 0.0248

Gnomad4 FIN exome AF: 0.00210

Gnomad4 NFE exome AF: 0.000424

Gnomad4 OTH exome AF: 0.00421

GnomAD4 genome AF: 0.00652 AC: 992 AN: 152242 Hom.: 23 Cov.: 33 AF XY: 0.00812 AC XY: 604 AN XY: 74430

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.0452

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0126

Gnomad4 SAS AF: 0.0263

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00137 Hom.: 2

Bravo AF: 0.00850

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.0107 AC: 1303

Asia WGS AF: 0.0200 AC: 70 AN: 3478

EpiCase AF: 0.000764

EpiControl AF: 0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2019	This variant is associated with the following publications: (PMID: 32719680, 31131138) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

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

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 22, 2023

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;T;D;.;T;T;T;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;D;.;D;D;D;D;D
MetaRNN	Benign	0.016	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.7	M;.;M;.;.;.;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.8	.;D;D;.;.;.;.;.
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	.;D;D;.;.;.;.;.
Sift4G	Uncertain	0.010	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;.;.;.;.
Vest4		0.35
MPC		0.91
ClinPred		0.059	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs146534657; hg19: chr6-138195991; COSMIC: COSV52799516; COSMIC: COSV52799516;