11-36503205-A-G

Variant names:

• chr11-36503205-A-G
• rs5030437
• NM_004620.4:c.-22-1668T>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.-22-1668T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.781 in 152,110 control chromosomes in the GnomAD database, including 47,239 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 0.78 (47239 hom., cov: 32)
• Consequence: TRAF6 NM_004620.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.220
• Publications: 18 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 (EAS) allele frequency at 95% confidence interval = 0.851 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.-22-1668T>C		intron	N/A	NP_004611.1	Q9Y4K3
	TRAF6	NM_145803.3		c.-115-1394T>C		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.-22-1668T>C		intron	N/A	ENSP00000433623.1	Q9Y4K3
	TRAF6	ENST00000348124.5	TSL:1	c.-115-1394T>C		intron	N/A	ENSP00000337853.5	Q9Y4K3
	TRAF6	ENST00000876418.1		c.-22-1668T>C		intron	N/A	ENSP00000546477.1

Frequencies

GnomAD3 genomes AF: 0.782 AC: 118798 AN: 151992 Hom.: 47227 Cov.: 32

Gnomad AFR AF: 0.622

Gnomad AMI AF: 0.926

Gnomad AMR AF: 0.863

Gnomad ASJ AF: 0.811

Gnomad EAS AF: 0.872

Gnomad SAS AF: 0.780

Gnomad FIN AF: 0.825

Gnomad MID AF: 0.826

Gnomad NFE AF: 0.843

Gnomad OTH AF: 0.793

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

GnomAD4 genome AF: 0.781 AC: 118856 AN: 152110 Hom.: 47239 Cov.: 32 AF XY: 0.784 AC XY: 58315 AN XY: 74344

African (AFR) AF: 0.622 AC: 25775 AN: 41456

American (AMR) AF: 0.863 AC: 13203 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.811 AC: 2814 AN: 3470

East Asian (EAS) AF: 0.872 AC: 4516 AN: 5178

South Asian (SAS) AF: 0.780 AC: 3758 AN: 4818

European-Finnish (FIN) AF: 0.825 AC: 8717 AN: 10568

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

European-Non Finnish (NFE) AF: 0.843 AC: 57307 AN: 68004

Other (OTH) AF: 0.794 AC: 1681 AN: 2116

Alfa AF: 0.819 Hom.: 115047

Bravo AF: 0.778

Asia WGS AF: 0.814 AC: 2831 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.9
DANN	Benign	0.69
PhyloP100		-0.22
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: rs5030437; hg19: chr11-36524755;