6-111591396-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_147686.4(TRAF3IP2):​c.691C>G​(p.Leu231Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000245 in 1,549,478 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000046 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

TRAF3IP2
NM_147686.4 missense

Scores

1
7
11

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.65
Variant links:
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)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.35721385).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TRAF3IP2NM_147686.4 linkc.691C>G p.Leu231Val missense_variant Exon 2 of 9 ENST00000368761.11 NP_679211.2 O43734-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TRAF3IP2ENST00000368761.11 linkc.691C>G p.Leu231Val missense_variant Exon 2 of 9 1 NM_147686.4 ENSP00000357750.5 O43734-2

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152188
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000303
AC:
6
AN:
197744
Hom.:
0
AF XY:
0.0000190
AC XY:
2
AN XY:
105292
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000409
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000532
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000222
AC:
31
AN:
1397172
Hom.:
0
Cov.:
31
AF XY:
0.0000261
AC XY:
18
AN XY:
689158
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000286
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152306
Hom.:
1
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74460
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jun 21, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.691C>G (p.L231V) alteration is located in exon 2 (coding exon 1) of the TRAF3IP2 gene. This alteration results from a C to G substitution at nucleotide position 691, causing the leucine (L) at amino acid position 231 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Candidiasis, familial, 8 Uncertain:1
Dec 22, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 231 of the TRAF3IP2 protein (p.Leu231Val). This variant is present in population databases (rs149860754, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with TRAF3IP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 957805). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TRAF3IP2 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
0.23
BayesDel_addAF
Benign
-0.084
T
BayesDel_noAF
Benign
-0.20
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.17
.;.;T;T
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Benign
0.74
D
LIST_S2
Uncertain
0.90
D;D;.;D
M_CAP
Benign
0.026
D
MetaRNN
Benign
0.36
T;T;T;T
MetaSVM
Benign
-0.73
T
MutationAssessor
Uncertain
2.6
.;.;M;M
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-1.3
N;N;N;.
REVEL
Benign
0.20
Sift
Pathogenic
0.0
D;D;D;.
Sift4G
Uncertain
0.017
D;D;D;D
Polyphen
1.0
D;.;D;D
Vest4
0.62
MutPred
0.083
.;.;Gain of phosphorylation at S242 (P = 0.3173);Gain of phosphorylation at S242 (P = 0.3173);
MVP
0.61
MPC
0.77
ClinPred
0.38
T
GERP RS
5.8
Varity_R
0.18
gMVP
0.17

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs149860754; hg19: chr6-111912599; API