chr14-102905586-C-T

Position:

• chr14-102905586-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_145725.3(TRAF3):​c.1509C>T​(p.Ser503Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,614,156 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (16 hom.)
• Consequence: TRAF3 NM_145725.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.480

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 14-102905586-C-T is Benign according to our data. Variant chr14-102905586-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 540501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-102905586-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.48 with no splicing effect.
• BS2: High AC in GnomAd4 at 410 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRAF3	NM_145725.3	c.1509C>T	p.Ser503Ser	synonymous_variant	12/12	ENST00000392745.8	NP_663777.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRAF3	ENST00000392745.8	c.1509C>T	p.Ser503Ser	synonymous_variant	12/12	1	NM_145725.3	ENSP00000376500.3

Frequencies

GnomAD3 genomes AF: 0.00270 AC: 411 AN: 152146 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00307

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00260 AC: 655 AN: 251486 Hom.: 2 AF XY: 0.00270 AC XY: 367 AN XY: 135916

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.0100

Gnomad NFE exome AF: 0.00304

Gnomad OTH exome AF: 0.00309

GnomAD4 exome AF: 0.00304 AC: 4437 AN: 1461892 Hom.: 16 Cov.: 31 AF XY: 0.00299 AC XY: 2175 AN XY: 727246

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.00975

Gnomad4 NFE exome AF: 0.00329

Gnomad4 OTH exome AF: 0.00235

GnomAD4 genome AF: 0.00269 AC: 410 AN: 152264 Hom.: 1 Cov.: 33 AF XY: 0.00294 AC XY: 219 AN XY: 74458

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0123

Gnomad4 NFE AF: 0.00306

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00229 Hom.: 0

Bravo AF: 0.00188

EpiCase AF: 0.00267

EpiControl AF: 0.00196

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TRAF3: BP4, BP7 -

Herpes simplex encephalitis, susceptibility to, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.2
DANN	Benign	0.47

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: rs138943371; hg19: chr14-103371923;