6-111591329-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_147686.4(TRAF3IP2):ā€‹c.758C>Gā€‹(p.Pro253Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 1,519,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.00015 ( 0 hom., cov: 32)
Exomes š‘“: 0.00017 ( 0 hom. )

Consequence

TRAF3IP2
NM_147686.4 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.112
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 Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.024632215).
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000151 (23/152278) while in subpopulation AMR AF= 0.000458 (7/15300). AF 95% confidence interval is 0.000215. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TRAF3IP2NM_147686.4 linkc.758C>G p.Pro253Arg missense_variant 2/9 ENST00000368761.11 NP_679211.2 O43734-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TRAF3IP2ENST00000368761.11 linkc.758C>G p.Pro253Arg missense_variant 2/91 NM_147686.4 ENSP00000357750.5 O43734-2

Frequencies

GnomAD3 genomes
AF:
0.000151
AC:
23
AN:
152160
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000458
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:
0.000206
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000212
AC:
38
AN:
179478
Hom.:
0
AF XY:
0.000244
AC XY:
23
AN XY:
94334
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000382
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:
0.000343
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000170
AC:
233
AN:
1367522
Hom.:
0
Cov.:
30
AF XY:
0.000180
AC XY:
121
AN XY:
670386
show subpopulations
Gnomad4 AFR exome
AF:
0.0000661
Gnomad4 AMR exome
AF:
0.000275
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000200
Gnomad4 NFE exome
AF:
0.000206
Gnomad4 OTH exome
AF:
0.0000356
GnomAD4 genome
AF:
0.000151
AC:
23
AN:
152278
Hom.:
0
Cov.:
32
AF XY:
0.000148
AC XY:
11
AN XY:
74442
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.000458
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000206
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000170
Hom.:
0
Bravo
AF:
0.000151
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000233
AC:
28

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Candidiasis, familial, 8 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 18, 2022This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 253 of the TRAF3IP2 protein (p.Pro253Arg). This variant is present in population databases (rs146627823, gnomAD 0.03%). 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: 541098). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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
0.095
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
11
DANN
Benign
0.96
DEOGEN2
Benign
0.35
.;.;T;T
Eigen
Benign
-0.56
Eigen_PC
Benign
-0.62
FATHMM_MKL
Benign
0.087
N
LIST_S2
Benign
0.63
T;T;.;T
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.025
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.4
.;.;M;M
PrimateAI
Benign
0.37
T
PROVEAN
Uncertain
-2.5
N;N;D;.
REVEL
Benign
0.070
Sift
Uncertain
0.017
D;D;D;.
Sift4G
Benign
0.069
T;T;T;T
Polyphen
0.57
P;.;B;B
Vest4
0.26
MVP
0.39
MPC
0.52
ClinPred
0.11
T
GERP RS
2.1
Varity_R
0.046
gMVP
0.26

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: rs146627823; hg19: chr6-111912532; API