rs547180445

Variant names:

• chr14-102870287-C-T
• rs547180445
• NM_145725.3:c.86C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_145725.3(TRAF3):​c.86C>T​(p.Thr29Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,614,182 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 (★). Synonymous variant affecting the same amino acid position (i.e. T29T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: TRAF3 NM_145725.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.23
• Publications: 2 publications found

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]

TRAF3 Gene-Disease associations (from GenCC):

• herpes simplex encephalitis, susceptibility to, 3

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• TRAF3 haploinsufficiency

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.045247078).
• BS2: High AC in GnomAdExome4 at 35 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145725.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAF3	NM_145725.3	MANE Select	c.86C>T	p.Thr29Met	missense	Exon 3 of 12	NP_663777.1	Q13114-1
	TRAF3	NM_003300.4		c.86C>T	p.Thr29Met	missense	Exon 2 of 11	NP_003291.2
	TRAF3	NM_145726.3		c.86C>T	p.Thr29Met	missense	Exon 3 of 11	NP_663778.1	A6NHG8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAF3	ENST00000392745.8	TSL:1 MANE Select	c.86C>T	p.Thr29Met	missense	Exon 3 of 12	ENSP00000376500.3	Q13114-1
	TRAF3	ENST00000560371.5	TSL:1	c.86C>T	p.Thr29Met	missense	Exon 2 of 11	ENSP00000454207.1	Q13114-1
	TRAF3	ENST00000351691.10	TSL:1	c.86C>T	p.Thr29Met	missense	Exon 3 of 11	ENSP00000332468.5	A6NHG8

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152178 Hom.: 0 Cov.: 32

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000716 AC: 18 AN: 251492 AF XY: 0.0000883

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000439

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 20 AN XY: 727244

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000224 AC: 10 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1112008

Other (OTH) AF: 0.0000993 AC: 6 AN: 60396

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74476

African (AFR) AF: 0.0000481 AC: 2 AN: 41556

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000906 AC: 11

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Herpes simplex encephalitis, susceptibility to, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.061
Sift	Benign	0.082	T
Sift4G	Benign	0.13	T
Polyphen		0.53	P
Vest4		0.18
MVP		0.20
MPC		0.72
ClinPred		0.013	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.065
gMVP		0.39
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: rs547180445; hg19: chr14-103336624; COSMIC: COSV61025161;