chr14-102870274-C-T
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2
The NM_145725.3(TRAF3):c.73C>T(p.Arg25Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
TRAF3
NM_145725.3 missense
NM_145725.3 missense
Scores
2
5
12
Clinical Significance
Conservation
PhyloP100: 4.41
Genes affected
TRAF3 (HGNC:12033): (TNF receptor associated factor 3) The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins associate with, and mediate the signal transduction from, members of the TNF receptor (TNFR) superfamily. This protein participates in the signal transduction of CD40, a TNFR family member important for the activation of the immune response. This protein is found to be a critical component of the lymphotoxin-beta receptor (LTbetaR) signaling complex, which induces NF-kappaB activation and cell death initiated by LTbeta ligation. Epstein-Barr virus encoded latent infection membrane protein-1 (LMP1) can interact with this and several other members of the TRAF family, which may be essential for the oncogenic effects of LMP1. The protein also plays a role in the regulation of antiviral response. Mutations in this are associated with Encephalopathy, acute, infection-induced, herpes-specific 5. [provided by RefSeq, Jul 2020]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TRAF3. . Gene score misZ 2.9892 (greater than the threshold 3.09). Trascript score misZ 4.4099 (greater than threshold 3.09). GenCC has associacion of gene with TRAF3 haploinsufficiency.
BP4
Computational evidence support a benign effect (MetaRNN=0.41014224).
BS2
High AC in GnomAdExome4 at 18 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TRAF3 | NM_145725.3 | c.73C>T | p.Arg25Cys | missense_variant | 3/12 | ENST00000392745.8 | NP_663777.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TRAF3 | ENST00000392745.8 | c.73C>T | p.Arg25Cys | missense_variant | 3/12 | 1 | NM_145725.3 | ENSP00000376500 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152184Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251494Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135922
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461894Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727248
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74346
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Herpes simplex encephalitis, susceptibility to, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 25 of the TRAF3 protein (p.Arg25Cys). This variant is present in population databases (no rsID available, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with TRAF3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1045822). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Benign
T;T;T;.;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;D;D;.
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;L;L;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N;N;N
REVEL
Benign
Sift
Pathogenic
D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D
Polyphen
D;D;D;D;.;D
Vest4
MutPred
Gain of catalytic residue at A27 (P = 0);Gain of catalytic residue at A27 (P = 0);Gain of catalytic residue at A27 (P = 0);Gain of catalytic residue at A27 (P = 0);Gain of catalytic residue at A27 (P = 0);Gain of catalytic residue at A27 (P = 0);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at