11-36497274-T-TA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_004620.4(TRAF6):c.448-9_448-8insT variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.829 in 1,591,132 control chromosomes in the GnomAD database, including 549,644 homozygotes. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.78 (47167 hom., cov: 0)
  • Exomes 𝑓: 0.83 (502477 hom.)
• Consequence: TRAF6 NM_004620.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign no assertion criteria provided B:2
• Conservation: PhyloP100: 2.03

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 -9 ACMG points.

• BP6: Variant 11-36497274-T-TA is Benign according to our data. Variant chr11-36497274-T-TA is described in ClinVar as [Benign]. Clinvar id is 1174623.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.851 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAF6	NM_004620.4	c.448-9_448-8insT		splice_polypyrimidine_tract_variant, intron_variant		ENST00000526995.6
TRAF6	NM_145803.3	c.448-9_448-8insT		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAF6	ENST00000526995.6	c.448-9_448-8insT		splice_polypyrimidine_tract_variant, intron_variant		1	NM_004620.4	P1
TRAF6	ENST00000348124.5	c.448-9_448-8insT		splice_polypyrimidine_tract_variant, intron_variant		1		P1

Frequencies

GnomAD3 genomes AF: 0.782 AC: 118634 AN: 151780 Hom.: 47155 Cov.: 0

Gnomad AFR AF: 0.622

Gnomad AMI AF: 0.927

Gnomad AMR AF: 0.863

Gnomad ASJ AF: 0.811

Gnomad EAS AF: 0.872

Gnomad SAS AF: 0.779

Gnomad FIN AF: 0.824

Gnomad MID AF: 0.826

Gnomad NFE AF: 0.843

Gnomad OTH AF: 0.793

GnomAD3 exomes AF: 0.825 AC: 194505 AN: 235818 Hom.: 80746 AF XY: 0.826 AC XY: 105679 AN XY: 127936

Gnomad AFR exome AF: 0.611

Gnomad AMR exome AF: 0.888

Gnomad ASJ exome AF: 0.794

Gnomad EAS exome AF: 0.876

Gnomad SAS exome AF: 0.782

Gnomad FIN exome AF: 0.832

Gnomad NFE exome AF: 0.841

Gnomad OTH exome AF: 0.839

GnomAD4 exome AF: 0.834 AC: 1200958 AN: 1439234 Hom.: 502477 Cov.: 33 AF XY: 0.834 AC XY: 596909 AN XY: 715700

Gnomad4 AFR exome AF: 0.605

Gnomad4 AMR exome AF: 0.886

Gnomad4 ASJ exome AF: 0.799

Gnomad4 EAS exome AF: 0.870

Gnomad4 SAS exome AF: 0.784

Gnomad4 FIN exome AF: 0.839

Gnomad4 NFE exome AF: 0.843

Gnomad4 OTH exome AF: 0.823

GnomAD4 genome AF: 0.781 AC: 118692 AN: 151898 Hom.: 47167 Cov.: 0 AF XY: 0.784 AC XY: 58220 AN XY: 74236

Gnomad4 AFR AF: 0.622

Gnomad4 AMR AF: 0.863

Gnomad4 ASJ AF: 0.811

Gnomad4 EAS AF: 0.872

Gnomad4 SAS AF: 0.779

Gnomad4 FIN AF: 0.824

Gnomad4 NFE AF: 0.843

Gnomad4 OTH AF: 0.794

Alfa AF: 0.781 Hom.: 5512

Bravo AF: 0.774

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Computational scores

Source: dbNSFP v4.3

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: rs3830511; hg19: chr11-36518824;