11-36488521-T-C

Variant names:

• chr11-36488521-T-C
• rs3740961
• NM_004620.4:c.*1317A>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.*1317A>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 0.131 in 152,696 control chromosomes in the GnomAD database, including 2,151 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 0.13 (2149 hom., cov: 32)
  • Exomes 𝑓: 0.10 (2 hom.)
• Consequence: TRAF6 NM_004620.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.39
• Publications: 4 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAF6	NM_004620.4	c.*1317A>G		3_prime_UTR_variant	Exon 7 of 7	ENST00000526995.6	NP_004611.1
TRAF6	NM_145803.3	c.*1317A>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.*1317A>G		3_prime_UTR_variant	Exon 7 of 7	1	NM_004620.4	ENSP00000433623.1

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19972 AN: 152036 Hom.: 2140 Cov.: 32

Gnomad AFR AF: 0.0491

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.530

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.0831

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.137

GnomAD4 exome AF: 0.0996 AC: 54 AN: 542 Hom.: 2 Cov.: 0 AF XY: 0.0840 AC XY: 22 AN XY: 262

African (AFR) AC: 0 AN: 0

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: 0.102 AC: 54 AN: 528

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 10

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.131 AC: 19992 AN: 152154 Hom.: 2149 Cov.: 32 AF XY: 0.137 AC XY: 10223 AN XY: 74390

African (AFR) AF: 0.0489 AC: 2033 AN: 41544

American (AMR) AF: 0.249 AC: 3798 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 531 AN: 3468

East Asian (EAS) AF: 0.530 AC: 2732 AN: 5156

South Asian (SAS) AF: 0.290 AC: 1391 AN: 4804

European-Finnish (FIN) AF: 0.0831 AC: 880 AN: 10592

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 8043 AN: 68004

Other (OTH) AF: 0.145 AC: 307 AN: 2110

Alfa AF: 0.135 Hom.: 2532

Bravo AF: 0.141

Asia WGS AF: 0.421 AC: 1462 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.43
DANN	Benign	0.35
PhyloP100		-1.4
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: rs3740961; hg19: chr11-36510071;