11-36506475-G-T

Variant names:

• chr11-36506475-G-T
• rs520074
• NM_004620.4:c.-23+3573C>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.-23+3573C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.975 in 152,264 control chromosomes in the GnomAD database, including 72,486 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 0.98 (72486 hom., cov: 31)
• Consequence: TRAF6 NM_004620.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.06
• Publications: 1 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=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 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.-23+3573C>A		intron	N/A	NP_004611.1
	TRAF6	NM_145803.3		c.-116+3573C>A		intron	N/A	NP_665802.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAF6	ENST00000526995.6	TSL:1 MANE Select	c.-23+3573C>A		intron	N/A	ENSP00000433623.1
	TRAF6	ENST00000348124.5	TSL:1	c.-116+3573C>A		intron	N/A	ENSP00000337853.5
	TRAF6	ENST00000876418.1		c.-23+3573C>A		intron	N/A	ENSP00000546477.1

Frequencies

GnomAD3 genomes AF: 0.975 AC: 148368 AN: 152146 Hom.: 72428 Cov.: 31

Gnomad AFR AF: 0.918

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.991

Gnomad ASJ AF: 0.994

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.970

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.980

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

GnomAD4 genome AF: 0.975 AC: 148485 AN: 152264 Hom.: 72486 Cov.: 31 AF XY: 0.976 AC XY: 72695 AN XY: 74474

African (AFR) AF: 0.919 AC: 38133 AN: 41512

American (AMR) AF: 0.991 AC: 15153 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.994 AC: 3449 AN: 3470

East Asian (EAS) AF: 0.997 AC: 5179 AN: 5192

South Asian (SAS) AF: 0.970 AC: 4688 AN: 4832

European-Finnish (FIN) AF: 1.00 AC: 10614 AN: 10614

Middle Eastern (MID) AF: 0.986 AC: 290 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67996 AN: 68040

Other (OTH) AF: 0.980 AC: 2071 AN: 2114

Alfa AF: 0.991 Hom.: 104227

Bravo AF: 0.973

Asia WGS AF: 0.972 AC: 3380 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.017
DANN	Benign	0.29
PhyloP100		-3.1
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: rs520074; hg19: chr11-36528025;