11-36503743-C-T

Variant names:

• chr11-36503743-C-T
• rs540386
• NM_004620.4:c.-22-2206G>A

Variant summary

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

The NM_004620.4(TRAF6):​c.-22-2206G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 152,056 control chromosomes in the GnomAD database, including 2,253 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 0.16 (2253 hom., cov: 32)
• Consequence: TRAF6 NM_004620.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.553
• Publications: 42 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAF6	NM_004620.4	c.-22-2206G>A		intron_variant	Intron 1 of 6	ENST00000526995.6	NP_004611.1
TRAF6	NM_145803.3	c.-115-1932G>A		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.-22-2206G>A		intron_variant	Intron 1 of 6	1	NM_004620.4	ENSP00000433623.1
TRAF6	ENST00000348124.5	c.-115-1932G>A		intron_variant	Intron 1 of 7	1		ENSP00000337853.5

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24911 AN: 151938 Hom.: 2251 Cov.: 32

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.0515

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.166

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

GnomAD4 genome AF: 0.164 AC: 24940 AN: 152056 Hom.: 2253 Cov.: 32 AF XY: 0.162 AC XY: 12060 AN XY: 74318

African (AFR) AF: 0.239 AC: 9892 AN: 41444

American (AMR) AF: 0.104 AC: 1582 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 560 AN: 3466

East Asian (EAS) AF: 0.0514 AC: 266 AN: 5174

South Asian (SAS) AF: 0.151 AC: 727 AN: 4820

European-Finnish (FIN) AF: 0.174 AC: 1835 AN: 10558

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9655 AN: 67996

Other (OTH) AF: 0.165 AC: 348 AN: 2114

Alfa AF: 0.137 Hom.: 1025

Bravo AF: 0.161

Asia WGS AF: 0.112 AC: 389 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.5
DANN	Benign	0.46
PhyloP100		0.55
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: rs540386; hg19: chr11-36525293;