11-36506475-G-T

Position:

• chr11-36506475-G-T

Variant summary

Our verdict is Benign. Variant got -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

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=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRAF6	NM_004620.4	c.-23+3573C>A		intron_variant		ENST00000526995.6	NP_004611.1
TRAF6	NM_145803.3	c.-116+3573C>A		intron_variant			NP_665802.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRAF6	ENST00000526995.6	c.-23+3573C>A		intron_variant		1	NM_004620.4	ENSP00000433623	P1
TRAF6	ENST00000348124.5	c.-116+3573C>A		intron_variant		1		ENSP00000337853	P1

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

Gnomad4 AFR AF: 0.919

Gnomad4 AMR AF: 0.991

Gnomad4 ASJ AF: 0.994

Gnomad4 EAS AF: 0.997

Gnomad4 SAS AF: 0.970

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.980

Alfa AF: 0.993 Hom.: 78392

Bravo AF: 0.973

Asia WGS AF: 0.972 AC: 3380 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.017
DANN	Benign	0.29

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: rs520074; hg19: chr11-36528025;