rs141920055

chr14-102876404-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_145725.3(TRAF3):c.449G>A(p.Arg150His) variant causes a missense change. The variant allele was found at a frequency of 0.000416 in 1,614,152 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00078 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (3 hom.)
• Consequence: TRAF3 NM_145725.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 5.39

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TRAF3
• BP4: Computational evidence support a benign effect (MetaRNN=0.005728811).
• BP6: Variant 14-102876404-G-A is Benign according to our data. Variant chr14-102876404-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252788.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.
• BS2: High AC in GnomAd at 119 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAF3	NM_145725.3	c.449G>A	p.Arg150His	missense_variant	6/12	ENST00000392745.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAF3	ENST00000392745.8	c.449G>A	p.Arg150His	missense_variant	6/12	1	NM_145725.3	P1

Frequencies

GnomAD3 genomes AF: 0.000782 AC: 119 AN: 152160 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000704 AC: 177 AN: 251470 Hom.: 1 AF XY: 0.000692 AC XY: 94 AN XY: 135918

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.0115

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000555

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000378 AC: 552 AN: 1461874 Hom.: 3 Cov.: 31 AF XY: 0.000373 AC XY: 271 AN XY: 727236

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.0122

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000452

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000809

Gnomad4 OTH exome AF: 0.000745

GnomAD4 genome AF: 0.000781 AC: 119 AN: 152278 Hom.: 1 Cov.: 33 AF XY: 0.000752 AC XY: 56 AN XY: 74458

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000607 Hom.: 2

Bravo AF: 0.000676

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000634 AC: 77

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Jul 30, 2015

- -

Herpes simplex encephalitis, susceptibility to, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

TRAF3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 05, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.47
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.037	T;T;T;.;T;.
Eigen	Benign	-0.017
Eigen_PC	Benign	0.10
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0057	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.59	N;.;N;N;.;.
MutationTaster	Benign	0.98	D;D;D;D;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	1.1	N;N;N;N;N;N
Sift	Benign	0.19	T;T;T;T;T;T
Sift4G	Benign	0.59	T;T;T;T;T;T
Polyphen		1.0	D;B;D;B;B;.
Vest4		0.24
MVP		0.38
MPC		0.77
ClinPred		0.014	T
GERP RS		5.7
Varity_R		0.082
gMVP		0.76

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: rs141920055; hg19: chr14-103342741;