11-36488476-T-C

Variant names:

• chr11-36488476-T-C
• rs5030482
• NM_004620.4:c.*1362A>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.*1362A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 152,906 control chromosomes in the GnomAD database, including 1,277 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 (1263 hom., cov: 31)
  • Exomes 𝑓: 0.16 (14 hom.)
• Consequence: TRAF6 NM_004620.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.453
• Publications: 7 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 = 0.15 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAF6	NM_004620.4	c.*1362A>G		3_prime_UTR_variant	Exon 7 of 7	ENST00000526995.6	NP_004611.1
TRAF6	NM_145803.3	c.*1362A>G		3_prime_UTR_variant	Exon 8 of 8		NP_665802.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAF6	ENST00000526995.6	c.*1362A>G		3_prime_UTR_variant	Exon 7 of 7	1	NM_004620.4	ENSP00000433623.1

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18529 AN: 151978 Hom.: 1261 Cov.: 31

Gnomad AFR AF: 0.0966

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0895

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.0386

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.126

GnomAD4 exome AF: 0.163 AC: 132 AN: 810 Hom.: 14 Cov.: 0 AF XY: 0.176 AC XY: 72 AN XY: 408

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.166 AC: 128 AN: 770

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.100 AC: 3 AN: 30

Other (OTH) AF: 0.125 AC: 1 AN: 8

GnomAD4 genome AF: 0.122 AC: 18538 AN: 152096 Hom.: 1263 Cov.: 31 AF XY: 0.122 AC XY: 9067 AN XY: 74350

African (AFR) AF: 0.0966 AC: 4009 AN: 41512

American (AMR) AF: 0.0893 AC: 1362 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 552 AN: 3468

East Asian (EAS) AF: 0.0390 AC: 202 AN: 5176

South Asian (SAS) AF: 0.160 AC: 769 AN: 4816

European-Finnish (FIN) AF: 0.176 AC: 1862 AN: 10562

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9449 AN: 67988

Other (OTH) AF: 0.125 AC: 264 AN: 2116

Alfa AF: 0.121 Hom.: 254

Bravo AF: 0.112

Asia WGS AF: 0.0870 AC: 301 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.64
PhyloP100		-0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs5030482; hg19: chr11-36510026;