11-36493896-A-G

Variant names:

• chr11-36493896-A-G
• rs5030470
• NM_004620.4:c.678+1080T>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.678+1080T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 152,276 control chromosomes in the GnomAD database, including 1,147 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 0.12 (1147 hom., cov: 32)
• Consequence: TRAF6 NM_004620.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.83
• Publications: 5 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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004620.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAF6	NM_004620.4	MANE Select	c.678+1080T>C		intron	N/A	NP_004611.1
	TRAF6	NM_145803.3		c.678+1080T>C		intron	N/A	NP_665802.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAF6	ENST00000526995.6	TSL:1 MANE Select	c.678+1080T>C		intron	N/A	ENSP00000433623.1
	TRAF6	ENST00000348124.5	TSL:1	c.678+1080T>C		intron	N/A	ENSP00000337853.5
	TRAF6	ENST00000529150.1	TSL:5	n.223+1080T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17526 AN: 152158 Hom.: 1146 Cov.: 32

Gnomad AFR AF: 0.0693

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0858

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.0521

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.173

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.123

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

GnomAD4 genome AF: 0.115 AC: 17528 AN: 152276 Hom.: 1147 Cov.: 32 AF XY: 0.115 AC XY: 8559 AN XY: 74450

African (AFR) AF: 0.0692 AC: 2876 AN: 41580

American (AMR) AF: 0.0857 AC: 1310 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 557 AN: 3472

East Asian (EAS) AF: 0.0520 AC: 270 AN: 5188

South Asian (SAS) AF: 0.151 AC: 727 AN: 4826

European-Finnish (FIN) AF: 0.173 AC: 1831 AN: 10588

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9633 AN: 68010

Other (OTH) AF: 0.123 AC: 259 AN: 2114

Alfa AF: 0.131 Hom.: 193

Bravo AF: 0.105

Asia WGS AF: 0.101 AC: 350 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	11
DANN	Benign	0.74
PhyloP100		2.8
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: rs5030470; hg19: chr11-36515446;