rs142350527

Positions:

• chr14-102870390-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_145725.3(TRAF3):​c.189G>A​(p.Pro63=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00471 in 1,614,160 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (49 hom.)
• Consequence: TRAF3 NM_145725.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.18

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 14-102870390-G-A is Benign according to our data. Variant chr14-102870390-G-A is described in ClinVar as [Benign]. Clinvar id is 473289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-102870390-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.18 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0046 (6726/1461832) while in subpopulation AMR AF= 0.0237 (1058/44720). AF 95% confidence interval is 0.0225. There are 49 homozygotes in gnomad4_exome. There are 3257 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 871 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAF3	NM_145725.3	c.189G>A	p.Pro63=	synonymous_variant	3/12	ENST00000392745.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAF3	ENST00000392745.8	c.189G>A	p.Pro63=	synonymous_variant	3/12	1	NM_145725.3	P1

Frequencies

GnomAD3 genomes AF: 0.00572 AC: 871 AN: 152210 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00988

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0372

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00382

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00815 AC: 2045 AN: 251054 Hom.: 27 AF XY: 0.00726 AC XY: 986 AN XY: 135744

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.0240

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00291

Gnomad FIN exome AF: 0.0318

Gnomad NFE exome AF: 0.00336

Gnomad OTH exome AF: 0.00588

GnomAD4 exome AF: 0.00460 AC: 6726 AN: 1461832 Hom.: 49 Cov.: 31 AF XY: 0.00448 AC XY: 3257 AN XY: 727216

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.0237

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00267

Gnomad4 FIN exome AF: 0.0320

Gnomad4 NFE exome AF: 0.00312

Gnomad4 OTH exome AF: 0.00353

GnomAD4 genome AF: 0.00572 AC: 871 AN: 152328 Hom.: 9 Cov.: 32 AF XY: 0.00717 AC XY: 534 AN XY: 74478

Gnomad4 AFR AF: 0.000962

Gnomad4 AMR AF: 0.00987

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0372

Gnomad4 NFE AF: 0.00382

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00389 Hom.: 1

Bravo AF: 0.00373

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00262

EpiControl AF: 0.00225

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Herpes simplex encephalitis, susceptibility to, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

TRAF3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 27, 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
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.9
DANN	Benign	0.89

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: rs142350527; hg19: chr14-103336727;