chr9-120911412-G-T

Position:

chr9-120911412-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005658.5(TRAF1):c.807C>A(p.Phe269Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,613,704 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00023 ( 1 hom. )

Consequence

TRAF1
NM_005658.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.27

Variant links:

Genes affected

TRAF1 (HGNC:12031): (TNF receptor associated factor 1) The protein encoded by this gene is a member of the TNF receptor (TNFR) associated factor (TRAF) protein family. TRAF proteins associate with, and mediate the signal transduction from various receptors of the TNFR superfamily. This protein and TRAF2 form a heterodimeric complex, which is required for TNF-alpha-mediated activation of MAPK8/JNK and NF-kappaB. The protein complex formed by this protein and TRAF2 also interacts with inhibitor-of-apoptosis proteins (IAPs), and thus mediates the anti-apoptotic signals from TNF receptors. The expression of this protein can be induced by Epstein-Barr virus (EBV). EBV infection membrane protein 1 (LMP1) is found to interact with this and other TRAF proteins; this interaction is thought to link LMP1-mediated B lymphocyte transformation to the signal transduction from TNFR family receptors. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

TRAF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.115382224).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRAF1	NM_005658.5 linkuse as main transcript	c.807C>A	p.Phe269Leu	missense_variant	6/8	ENST00000373887.8	NP_005649.1	Q13077-1
TRAF1	NM_001190945.2 linkuse as main transcript	c.807C>A	p.Phe269Leu	missense_variant	7/9		NP_001177874.1	Q13077-1
TRAF1	NM_001190947.2 linkuse as main transcript	c.441C>A	p.Phe147Leu	missense_variant	4/6		NP_001177876.1	Q13077-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TRAF1	ENST00000373887.8 linkuse as main transcript	c.807C>A	p.Phe269Leu	missense_variant	6/8	1	NM_005658.5	ENSP00000362994.3	Q13077-1
TRAF1	ENST00000540010.1 linkuse as main transcript	c.807C>A	p.Phe269Leu	missense_variant	7/9	1		ENSP00000443183.1	Q13077-1
TRAF1	ENST00000546084.5 linkuse as main transcript	c.441C>A	p.Phe147Leu	missense_variant	4/6	2		ENSP00000438583.1	Q13077-2

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

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:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000996

AC:

AN:

250914

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000225

AC:

329

AN:

1461346

Hom.:

Cov.:

AF XY:

0.000205

AC XY:

149

AN XY:

726964

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000261

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000171

AC:

AN:

152358

Hom.:

Cov.:

AF XY:

0.000174

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.000216

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000201

Hom.:

Bravo

AF:

0.000162

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 09, 2024

The c.807C>A (p.F269L) alteration is located in exon 6 (coding exon 5) of the TRAF1 gene. This alteration results from a C to A substitution at nucleotide position 807, causing the phenylalanine (F) at amino acid position 269 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.21

.;T;T

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.89

D;.;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.38

.;N;N

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-2.5

D;D;D

REVEL

Benign

0.20

Sift

Benign

0.59

T;T;T

Sift4G

Benign

0.85

T;T;T

Polyphen

0.65

.;P;P

Vest4

0.44

MutPred

0.49

.;Gain of catalytic residue at F269 (P = 0.0039);Gain of catalytic residue at F269 (P = 0.0039);

MVP

0.34

MPC

0.39

ClinPred

0.028

GERP RS

3.7

Varity_R

0.53

gMVP

0.88

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over