rs16928973

Variant names:

• chr11-36492695-C-T
• rs16928973
• NM_004620.4:c.679-67G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 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=-0.76).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.064 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAF6	NM_004620.4	MANE Select	c.679-67G>A		intron	N/A	NP_004611.1
	TRAF6	NM_145803.3		c.679-67G>A		intron	N/A	NP_665802.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAF6	ENST00000526995.6	TSL:1 MANE Select	c.679-67G>A		intron	N/A	ENSP00000433623.1
	TRAF6	ENST00000348124.5	TSL:1	c.679-67G>A		intron	N/A	ENSP00000337853.5
	TRAF6	ENST00000529150.1	TSL:5	n.224-67G>A		intron	N/A

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

African (AFR) AF: 0.00352 AC: 86 AN: 24458

American (AMR) AF: 0.0300 AC: 1088 AN: 36232

Ashkenazi Jewish (ASJ) AF: 0.0223 AC: 496 AN: 22274

East Asian (EAS) AF: 0.0797 AC: 3013 AN: 37794

South Asian (SAS) AF: 0.0177 AC: 1307 AN: 73656

European-Finnish (FIN) AF: 0.00249 AC: 131 AN: 52510

Middle Eastern (MID) AF: 0.0105 AC: 49 AN: 4646

European-Non Finnish (NFE) AF: 0.0153 AC: 11766 AN: 771198

Other (OTH) AF: 0.0147 AC: 692 AN: 47044

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

African (AFR) AF: 0.00284 AC: 118 AN: 41556

American (AMR) AF: 0.0149 AC: 228 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3470

East Asian (EAS) AF: 0.0699 AC: 362 AN: 5178

South Asian (SAS) AF: 0.0228 AC: 110 AN: 4820

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10608

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0146 AC: 993 AN: 68026

Other (OTH) AF: 0.0119 AC: 25 AN: 2108

Alfa AF: 0.0145 Hom.: 43

Bravo AF: 0.0146

Asia WGS AF: 0.0330 AC: 115 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.4
DANN	Benign	0.71
PhyloP100		-0.65
Mutation Taster		=100/0	polymorphism

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: rs16928973; hg19: chr11-36514245;