rs1131877

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_145725.3(TRAF3):c.386T>C(p.Met129Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,613,126 control chromosomes in the GnomAD database, including 75,647 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M129V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.42 ( 18835 hom., cov: 32)

Exomes 𝑓: 0.26 ( 56812 hom. )

Consequence

TRAF3
NM_145725.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.04

Publications

56 publications found

Variant links:

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):

TRAF3 haploinsufficiency
Inheritance: AD Classification: MODERATE Submitted by: ClinGen

TRAF3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.739789E-7).

BP6

Variant 14-102875712-T-C is Benign according to our data. Variant chr14-102875712-T-C is described in ClinVar as Benign. ClinVar VariationId is 1168583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.82 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAF3	NM_145725.3 link	c.386T>C	p.Met129Thr	missense_variant	Exon 5 of 12	ENST00000392745.8	NP_663777.1	Q13114-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAF3	ENST00000392745.8 link	c.386T>C	p.Met129Thr	missense_variant	Exon 5 of 12	1	NM_145725.3	ENSP00000376500.3		Q13114-1

Frequencies

GnomAD3 genomes

AF:

0.423

AC:

64375

AN:

152016

Hom.:

18766

Cov.:

show subpopulations

Gnomad AFR

AF:

0.827

Gnomad AMI

AF:

0.362

Gnomad AMR

AF:

0.408

Gnomad ASJ

AF:

0.310

Gnomad EAS

AF:

0.405

Gnomad SAS

AF:

0.176

Gnomad FIN

AF:

0.297

Gnomad MID

AF:

0.174

Gnomad NFE

AF:

0.229

Gnomad OTH

AF:

0.380

GnomAD2 exomes

AF:

0.315

AC:

79290

AN:

251442

AF XY:

0.292

show subpopulations

Gnomad AFR exome

AF:

0.835

Gnomad AMR exome

AF:

0.448

Gnomad ASJ exome

AF:

0.315

Gnomad EAS exome

AF:

0.402

Gnomad FIN exome

AF:

0.295

Gnomad NFE exome

AF:

0.231

Gnomad OTH exome

AF:

0.275

GnomAD4 exome

AF:

0.255

AC:

372710

AN:

1460992

Hom.:

56812

Cov.:

AF XY:

0.250

AC XY:

181810

AN XY:

726850

show subpopulations

African (AFR)

AF:

0.845

AC:

28292

AN:

33468

American (AMR)

AF:

0.449

AC:

20067

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.316

AC:

8245

AN:

26122

East Asian (EAS)

AF:

0.416

AC:

16496

AN:

39666

South Asian (SAS)

AF:

0.172

AC:

14854

AN:

86244

European-Finnish (FIN)

AF:

0.292

AC:

15611

AN:

53382

Middle Eastern (MID)

AF:

0.192

AC:

1104

AN:

5764

European-Non Finnish (NFE)

AF:

0.226

AC:

251054

AN:

1111286

Other (OTH)

AF:

0.282

AC:

16987

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

12875

25751

38626

51502

64377

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8986

17972

26958

35944

44930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.424

AC:

64512

AN:

152134

Hom.:

18835

Cov.:

AF XY:

0.421

AC XY:

31351

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.827

AC:

34359

AN:

41526

American (AMR)

AF:

0.409

AC:

6242

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.310

AC:

1075

AN:

3470

East Asian (EAS)

AF:

0.405

AC:

2096

AN:

5172

South Asian (SAS)

AF:

0.175

AC:

842

AN:

4820

European-Finnish (FIN)

AF:

0.297

AC:

3141

AN:

10584

Middle Eastern (MID)

AF:

0.177

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.229

AC:

15574

AN:

67982

Other (OTH)

AF:

0.381

AC:

802

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1404

2809

4213

5618

7022

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

522

1044

1566

2088

2610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.298

Hom.:

26752

Bravo

AF:

0.456

TwinsUK

AF:

0.230

AC:

851

ALSPAC

AF:

0.234

AC:

901

ESP6500AA

AF:

0.818

AC:

3603

ESP6500EA

AF:

0.233

AC:

2000

ExAC

AF:

0.316

AC:

38301

Asia WGS

AF:

0.331

AC:

1150

AN:

3478

EpiCase

AF:

0.218

EpiControl

AF:

0.226

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 72% of patients studied by a panel of primary immunodeficiencies. Number of patients: 68. Only high quality variants are reported. -

Herpes simplex encephalitis, susceptibility to, 3

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.046

T;T;T;.;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0047

LIST_S2

Benign

0.011

.;T;T;T;.;T

MetaRNN

Benign

5.7e-7

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.8

N;.;N;N;.;.

PhyloP100

2.0

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.26

N;N;N;N;N;N

REVEL

Benign

0.059

Sift

Benign

0.85

T;T;T;T;T;T

Sift4G

Benign

0.72

T;T;T;T;T;T

Polyphen

0.0

B;B;B;B;B;.

Vest4

0.012

MPC

0.65

ClinPred

0.00063

GERP RS

3.6

PromoterAI

0.0036

Neutral

(source)

Varity_R

0.050

gMVP

0.61

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over