6-111575786-C-G

Variant names:

• chr6-111575786-C-G
• rs148619849
• NM_147686.4:c.1058G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_147686.4(TRAF3IP2):​c.1058G>C​(p.Gly353Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,264 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G353D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TRAF3IP2 NM_147686.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19
• Publications: 1 publications found

Genes affected

TRAF3IP2 (HGNC:1343): (TRAF3 interacting protein 2) This gene encodes a protein involved in regulating responses to cytokines by members of the Rel/NF-kappaB transcription factor family. These factors play a central role in innate immunity in response to pathogens, inflammatory signals and stress. This gene product interacts with TRAF proteins (tumor necrosis factor receptor-associated factors) and either I-kappaB kinase or MAP kinase to activate either NF-kappaB or Jun kinase. Several alternative transcripts encoding different isoforms have been identified. Another transcript, which does not encode a protein and is transcribed in the opposite orientation, has been identified. Overexpression of this transcript has been shown to reduce expression of at least one of the protein encoding transcripts, suggesting it has a regulatory role in the expression of this gene. [provided by RefSeq, Aug 2009]

TRAF3IP2-AS1 (HGNC:40005): (TRAF3IP2 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06434211).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAF3IP2	NM_147686.4	c.1058G>C	p.Gly353Ala	missense_variant	Exon 4 of 9	ENST00000368761.11	NP_679211.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAF3IP2	ENST00000368761.11	c.1058G>C	p.Gly353Ala	missense_variant	Exon 4 of 9	1	NM_147686.4	ENSP00000357750.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457264 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 725086

African (AFR) AF: 0.00 AC: 0 AN: 33132

American (AMR) AF: 0.00 AC: 0 AN: 43218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25940

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.00 AC: 0 AN: 85560

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5624

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110602

Other (OTH) AF: 0.00 AC: 0 AN: 60208

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Candidiasis, familial, 8 Uncertain:1

Aug 24, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine with alanine at codon 353 of the TRAF3IP2 protein (p.Gly353Ala). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and alanine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with psoriatic arthritis (PMID: 22513239). ClinVar contains an entry for this variant (Variation ID: 574786). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	7.6
DANN	Benign	0.56
DEOGEN2	Benign	0.052	.;.;T;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.68	T;T;.;T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.064	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.9	.;.;L;L
PhyloP100		1.2
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.030	N;N;N;.
REVEL	Benign	0.027
Sift	Benign	0.59	T;T;T;.
Sift4G	Benign	0.79	T;T;T;T
Polyphen		0.0030	B;.;B;B
Vest4		0.22
MutPred		0.20		.;.;Loss of catalytic residue at G362 (P = 0.022);Loss of catalytic residue at G362 (P = 0.022);
MVP		0.32
MPC		0.22
ClinPred		0.045	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.019
gMVP		0.32
Mutation Taster		=99/1	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

Other links and lift over

dbSNP: rs148619849; hg19: chr6-111896989;