11-36509094-C-G

Variant names:

• chr11-36509094-C-G
• rs4755453
• NM_004620.4:c.-23+954G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004620.4(TRAF6):​c.-23+954G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.728 in 152,122 control chromosomes in the GnomAD database, including 42,755 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.73 (42755 hom., cov: 32)
• Consequence: TRAF6 NM_004620.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.524
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant hypohidrotic ectodermal dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.849 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAF6	NM_004620.4	c.-23+954G>C		intron_variant	Intron 1 of 6	ENST00000526995.6	NP_004611.1
TRAF6	NM_145803.3	c.-116+954G>C		intron_variant	Intron 1 of 7		NP_665802.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAF6	ENST00000526995.6	c.-23+954G>C		intron_variant	Intron 1 of 6	1	NM_004620.4	ENSP00000433623.1
TRAF6	ENST00000348124.5	c.-116+954G>C		intron_variant	Intron 1 of 7	1		ENSP00000337853.5

Frequencies

GnomAD3 genomes AF: 0.728 AC: 110678 AN: 152004 Hom.: 42753 Cov.: 32

Gnomad AFR AF: 0.439

Gnomad AMI AF: 0.927

Gnomad AMR AF: 0.843

Gnomad ASJ AF: 0.811

Gnomad EAS AF: 0.870

Gnomad SAS AF: 0.768

Gnomad FIN AF: 0.825

Gnomad MID AF: 0.813

Gnomad NFE AF: 0.841

Gnomad OTH AF: 0.753

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.728 AC: 110705 AN: 152122 Hom.: 42755 Cov.: 32 AF XY: 0.732 AC XY: 54439 AN XY: 74376

African (AFR) AF: 0.439 AC: 18186 AN: 41454

American (AMR) AF: 0.843 AC: 12880 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.811 AC: 2815 AN: 3470

East Asian (EAS) AF: 0.871 AC: 4506 AN: 5176

South Asian (SAS) AF: 0.768 AC: 3705 AN: 4826

European-Finnish (FIN) AF: 0.825 AC: 8731 AN: 10588

Middle Eastern (MID) AF: 0.806 AC: 237 AN: 294

European-Non Finnish (NFE) AF: 0.841 AC: 57208 AN: 68016

Other (OTH) AF: 0.755 AC: 1592 AN: 2110

Alfa AF: 0.704 Hom.: 2326

Bravo AF: 0.719

Asia WGS AF: 0.791 AC: 2754 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.1
DANN	Benign	0.48
PhyloP100		0.52
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4755453; hg19: chr11-36530644;