rs5029941

Positions:

• chr6-137874923-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001270508.2(TNFAIP3):​c.374C>T​(p.Ala125Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000935 in 1,614,222 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0053 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (7 hom.)
• Consequence: TNFAIP3 NM_001270508.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1 O:1
• Conservation: PhyloP100: 2.81

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010955274).
• BP6: Variant 6-137874923-C-T is Benign according to our data. Variant chr6-137874923-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135332.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00528 (805/152330) while in subpopulation AFR AF= 0.0184 (764/41570). AF 95% confidence interval is 0.0173. There are 8 homozygotes in gnomad4. There are 380 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 805 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFAIP3	NM_001270508.2	c.374C>T	p.Ala125Val	missense_variant	3/9	ENST00000612899.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFAIP3	ENST00000612899.5	c.374C>T	p.Ala125Val	missense_variant	3/9	5	NM_001270508.2	P1

Frequencies

GnomAD3 genomes AF: 0.00528 AC: 804 AN: 152212 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00120 AC: 303 AN: 251472 Hom.: 3 AF XY: 0.000876 AC XY: 119 AN XY: 135906

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.000482 AC: 704 AN: 1461892 Hom.: 7 Cov.: 33 AF XY: 0.000430 AC XY: 313 AN XY: 727246

Gnomad4 AFR exome AF: 0.0173

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.00528 AC: 805 AN: 152330 Hom.: 8 Cov.: 33 AF XY: 0.00510 AC XY: 380 AN XY: 74488

Gnomad4 AFR AF: 0.0184

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00112 Hom.: 4

Bravo AF: 0.00570

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0163 AC: 72

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00166 AC: 201

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 13, 2015	- -

Autoinflammatory syndrome, familial, Behcet-like Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 18, 2021

The TNFAIP3 c.374C>T; p.Ala125Val variant (rs5029941), to our knowledge, has not been reported in individuals with Behcet-like autoinflammatory syndrome but has been reported to mediate risk for other inflammatory related disorders (Lodolce 2010). Functional analyses of the variant protein show diminished deubiquitination and degradation activity, although it is unclear whether this results in increased or decreased inflammation (Lodolce 2010). This variant is also reported in ClinVar (Variation ID: 135332). This variant is found in the African population with an allele frequency of 1.7% (434/24970 alleles, including 4 homozygotes) in the Genome Aggregation Database. The alanine at codon 125 is moderately conserved, but computational analyses predict that this variant is neutral (REVEL: 0.078). Although the population frequency of this variant is relatively high, the possibility of reduced penetrance or a mild effect cannot be excluded. Therefore, due to a lack of clinical and functional data, the significance of this variant cannot be determined with certainty. Reference Lodolce JP et al. African-derived genetic polymorphisms in TNFAIP3 mediate risk for autoimmunity. J Immunol. 2010 Jun 15;184(12):7001-9. PMID: 20483768. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T;T;.;T;T;T;.
Eigen	Benign	0.010
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.81	T;T;.;T;T;T;T;T
MetaRNN	Benign	0.011	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.;L;.;.;.;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.39	T
Sift4G	Benign	0.10	T;T;T;T;T;T;T;T
Polyphen		0.98	D;.;D;.;.;.;.;.
Vest4		0.26
MVP		0.25
MPC		0.32
ClinPred		0.045	T
GERP RS		4.2
Varity_R		0.13
gMVP		0.50

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: rs5029941; hg19: chr6-138196060;