11-36497235-A-G

Position:

chr11-36497235-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_004620.4(TRAF6):c.479T>C(p.Met160Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000955 in 1,612,576 control chromosomes in the GnomAD database, including 4 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 Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 4 hom. )

Consequence

TRAF6
NM_004620.4 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.31

Variant links:

Genes affected

TRAF6 (HGNC:12036): (TNF receptor associated factor 6) The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins are associated with, and mediate signal transduction from, members of the TNF receptor superfamily. This protein has an amino terminal RING domain which is followed by four zinc-finger motifs, a central coiled-coil region and a highly conserved carboxyl terminal domain, known as the TRAF-C domain and mediates signaling from members of the TNF receptor superfamily as well as the Toll/IL-1 family. Signals from receptors such as CD40, TNFSF11/RANCE and IL-1 have been shown to be mediated by this protein. This protein also interacts with various protein kinases including IRAK1/IRAK, SRC and PKCzeta, which provides a link between distinct signaling pathways. This protein functions as a signal transducer in the NF-kappaB pathway that activates IkappaB kinase (IKK) in response to proinflammatory cytokines. The interaction of this protein with UBE2N/UBC13, and UBE2V1/UEV1A, which are ubiquitin conjugating enzymes catalyzing the formation of polyubiquitin chains, has been found to be required for IKK activation by this protein. This protein also interacts with the transforming growth factor (TGF) beta receptor complex and is required for Smad-independent activation of the JNK and p38 kinases. The protein encoded by this gene is a key molecule in antiviral innate and antigen-specific immune responses. [provided by RefSeq, Nov 2021]

TRAF6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TRAF6. . Gene score misZ 2.7157 (greater than the threshold 3.09). Trascript score misZ 4.018 (greater than threshold 3.09). GenCC has associacion of gene with autosomal dominant hypohidrotic ectodermal dysplasia.

BP4

Computational evidence support a benign effect (MetaRNN=0.0073675215).

BP6

Variant 11-36497235-A-G is Benign according to our data. Variant chr11-36497235-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3045430.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 82 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRAF6	NM_004620.4 linkuse as main transcript	c.479T>C	p.Met160Thr	missense_variant	4/7	ENST00000526995.6	NP_004611.1
TRAF6	NM_145803.3 linkuse as main transcript	c.479T>C	p.Met160Thr	missense_variant	5/8		NP_665802.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRAF6	ENST00000526995.6 linkuse as main transcript	c.479T>C	p.Met160Thr	missense_variant	4/7	1	NM_004620.4	ENSP00000433623	P1
TRAF6	ENST00000348124.5 linkuse as main transcript	c.479T>C	p.Met160Thr	missense_variant	5/8	1		ENSP00000337853	P1

Frequencies

GnomAD3 genomes

AF:

0.000535

AC:

AN:

151352

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000267

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000333

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00146

Gnomad FIN

AF:

0.0000951

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000795

Gnomad OTH

AF:

0.00145

GnomAD3 exomes

AF:

0.000835

AC:

208

AN:

249150

Hom.:

AF XY:

0.000994

AC XY:

134

AN XY:

134752

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.000178

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000220

Gnomad SAS exome

AF:

0.00265

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000981

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.000998

AC:

1458

AN:

1461106

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

789

AN XY:

726844

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000337

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00265

Gnomad4 FIN exome

AF:

0.000187

Gnomad4 NFE exome

AF:

0.00101

Gnomad4 OTH exome

AF:

0.00108

GnomAD4 genome

AF:

0.000541

AC:

AN:

151470

Hom.:

Cov.:

AF XY:

0.000446

AC XY:

AN XY:

73952

show subpopulations

Gnomad4 AFR

AF:

0.000266

Gnomad4 AMR

AF:

0.000333

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00167

Gnomad4 FIN

AF:

0.0000951

Gnomad4 NFE

AF:

0.000795

Gnomad4 OTH

AF:

0.00144

Alfa

AF:

0.000787

Hom.:

Bravo

AF:

0.000578

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000988

AC:

120

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000874

EpiControl

AF:

0.00125

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

TRAF6-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2024

This variant is classified as likely 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

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Benign

0.74

DEOGEN2

Benign

0.17

T;T

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.45

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.62

.;T

M_CAP

Benign

0.0057

MetaRNN

Benign

0.0074

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.91

N;N

REVEL

Benign

0.088

Sift

Benign

0.26

T;T

Sift4G

Benign

0.37

T;T

Polyphen

0.0

B;B

Vest4

0.20

MVP

0.21

MPC

0.78

ClinPred

0.0073

GERP RS

1.3

Varity_R

0.18

gMVP

0.59

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