11-36500710-T-C

Variant names:

• chr11-36500710-T-C
• rs5030445
• NM_004620.4:c.296+510A>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.296+510A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.767 in 151,934 control chromosomes in the GnomAD database, including 45,894 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 (45894 hom., cov: 30)
• Consequence: TRAF6 NM_004620.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.449
• Publications: 13 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=-0.77).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.852 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAF6	NM_004620.4	MANE Select	c.296+510A>G		intron	N/A	NP_004611.1	Q9Y4K3
	TRAF6	NM_145803.3		c.296+510A>G		intron	N/A	NP_665802.1	Q9Y4K3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAF6	ENST00000526995.6	TSL:1 MANE Select	c.296+510A>G		intron	N/A	ENSP00000433623.1	Q9Y4K3
	TRAF6	ENST00000348124.5	TSL:1	c.296+510A>G		intron	N/A	ENSP00000337853.5	Q9Y4K3
	TRAF6	ENST00000876418.1		c.296+510A>G		intron	N/A	ENSP00000546477.1

Frequencies

GnomAD3 genomes AF: 0.767 AC: 116468 AN: 151816 Hom.: 45885 Cov.: 30

Gnomad AFR AF: 0.572

Gnomad AMI AF: 0.926

Gnomad AMR AF: 0.857

Gnomad ASJ AF: 0.811

Gnomad EAS AF: 0.873

Gnomad SAS AF: 0.779

Gnomad FIN AF: 0.824

Gnomad MID AF: 0.825

Gnomad NFE AF: 0.843

Gnomad OTH AF: 0.782

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

GnomAD4 genome AF: 0.767 AC: 116516 AN: 151934 Hom.: 45894 Cov.: 30 AF XY: 0.770 AC XY: 57222 AN XY: 74268

African (AFR) AF: 0.572 AC: 23661 AN: 41394

American (AMR) AF: 0.857 AC: 13075 AN: 15258

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

East Asian (EAS) AF: 0.873 AC: 4488 AN: 5138

South Asian (SAS) AF: 0.779 AC: 3749 AN: 4814

European-Finnish (FIN) AF: 0.824 AC: 8713 AN: 10574

Middle Eastern (MID) AF: 0.822 AC: 240 AN: 292

European-Non Finnish (NFE) AF: 0.843 AC: 57282 AN: 67978

Other (OTH) AF: 0.784 AC: 1652 AN: 2108

Alfa AF: 0.809 Hom.: 14472

Bravo AF: 0.762

Asia WGS AF: 0.809 AC: 2816 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.4
DANN	Benign	0.86
PhyloP100		0.45
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: rs5030445; hg19: chr11-36522260;