11-36492740-T-C

Variant names:

• chr11-36492740-T-C
• rs2303439
• NM_004620.4:c.679-112A>G

Variant summary

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

The NM_004620.4(TRAF6):​c.679-112A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.823 in 765,826 control chromosomes in the GnomAD database, including 261,797 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 0.77 (46269 hom., cov: 31)
  • Exomes 𝑓: 0.84 (215528 hom.)
• Consequence: TRAF6 NM_004620.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.19
• Publications: 12 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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.853 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAF6	NM_004620.4	c.679-112A>G		intron_variant	Intron 5 of 6	ENST00000526995.6	NP_004611.1
TRAF6	NM_145803.3	c.679-112A>G		intron_variant	Intron 6 of 7		NP_665802.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAF6	ENST00000526995.6	c.679-112A>G		intron_variant	Intron 5 of 6	1	NM_004620.4	ENSP00000433623.1
TRAF6	ENST00000348124.5	c.679-112A>G		intron_variant	Intron 6 of 7	1		ENSP00000337853.5
TRAF6	ENST00000529150.1	n.224-112A>G		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes AF: 0.771 AC: 117102 AN: 151946 Hom.: 46262 Cov.: 31

Gnomad AFR AF: 0.581

Gnomad AMI AF: 0.927

Gnomad AMR AF: 0.859

Gnomad ASJ AF: 0.811

Gnomad EAS AF: 0.875

Gnomad SAS AF: 0.808

Gnomad FIN AF: 0.825

Gnomad MID AF: 0.826

Gnomad NFE AF: 0.843

Gnomad OTH AF: 0.784

GnomAD4 exome AF: 0.836 AC: 513148 AN: 613762 Hom.: 215528 AF XY: 0.836 AC XY: 273838 AN XY: 327510

African (AFR) AF: 0.574 AC: 8845 AN: 15414

American (AMR) AF: 0.887 AC: 22725 AN: 25630

Ashkenazi Jewish (ASJ) AF: 0.801 AC: 13384 AN: 16716

East Asian (EAS) AF: 0.873 AC: 30413 AN: 34846

South Asian (SAS) AF: 0.817 AC: 45325 AN: 55468

European-Finnish (FIN) AF: 0.842 AC: 40176 AN: 47728

Middle Eastern (MID) AF: 0.832 AC: 2289 AN: 2750

European-Non Finnish (NFE) AF: 0.844 AC: 324218 AN: 383924

Other (OTH) AF: 0.824 AC: 25773 AN: 31286

GnomAD4 genome AF: 0.770 AC: 117147 AN: 152064 Hom.: 46269 Cov.: 31 AF XY: 0.775 AC XY: 57570 AN XY: 74330

African (AFR) AF: 0.580 AC: 24015 AN: 41410

American (AMR) AF: 0.859 AC: 13124 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.811 AC: 2813 AN: 3470

East Asian (EAS) AF: 0.875 AC: 4525 AN: 5174

South Asian (SAS) AF: 0.807 AC: 3893 AN: 4822

European-Finnish (FIN) AF: 0.825 AC: 8730 AN: 10586

Middle Eastern (MID) AF: 0.823 AC: 242 AN: 294

European-Non Finnish (NFE) AF: 0.843 AC: 57300 AN: 68004

Other (OTH) AF: 0.786 AC: 1660 AN: 2112

Alfa AF: 0.816 Hom.: 16666

Bravo AF: 0.765

Asia WGS AF: 0.834 AC: 2900 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.17
DANN	Benign	0.42
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2303439; hg19: chr11-36514290; COSMIC: COSV61922498;