rs16928973

Positions:

• chr11-36492695-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004620.4(TRAF6):​c.679-67G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0169 in 1,222,076 control chromosomes in the GnomAD database, including 310 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 0.013 (31 hom., cov: 32)
  • Exomes 𝑓: 0.017 (279 hom.)
• Consequence: TRAF6 NM_004620.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.651

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.064 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAF6	NM_004620.4	c.679-67G>A		intron_variant		ENST00000526995.6
TRAF6	NM_145803.3	c.679-67G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAF6	ENST00000526995.6	c.679-67G>A		intron_variant		1	NM_004620.4	P1
TRAF6	ENST00000348124.5	c.679-67G>A		intron_variant		1		P1
TRAF6	ENST00000529150.1	n.224-67G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1969 AN: 152146 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.00285

Gnomad AMI AF: 0.0385

Gnomad AMR AF: 0.0149

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.0699

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.0120

GnomAD4 exome AF: 0.0174 AC: 18628 AN: 1069812 Hom.: 279 AF XY: 0.0172 AC XY: 9438 AN XY: 548742

Gnomad4 AFR exome AF: 0.00352

Gnomad4 AMR exome AF: 0.0300

Gnomad4 ASJ exome AF: 0.0223

Gnomad4 EAS exome AF: 0.0797

Gnomad4 SAS exome AF: 0.0177

Gnomad4 FIN exome AF: 0.00249

Gnomad4 NFE exome AF: 0.0153

Gnomad4 OTH exome AF: 0.0147

GnomAD4 genome AF: 0.0129 AC: 1969 AN: 152264 Hom.: 31 Cov.: 32 AF XY: 0.0127 AC XY: 943 AN XY: 74440

Gnomad4 AFR AF: 0.00284

Gnomad4 AMR AF: 0.0149

Gnomad4 ASJ AF: 0.0216

Gnomad4 EAS AF: 0.0699

Gnomad4 SAS AF: 0.0228

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.0146

Gnomad4 OTH AF: 0.0119

Alfa AF: 0.0144 Hom.: 19

Bravo AF: 0.0146

Asia WGS AF: 0.0330 AC: 115 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.4
DANN	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs16928973; hg19: chr11-36514245;