rs5030461

Variant names:

• chr11-36495606-T-C
• rs5030461
• NM_004620.4:c.607-559A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004620.4(TRAF6):​c.607-559A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0283 in 151,920 control chromosomes in the GnomAD database, including 206 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 0.028 (206 hom., cov: 32)
• Consequence: TRAF6 NM_004620.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00100
• 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0936 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAF6	NM_004620.4	c.607-559A>G		intron_variant	Intron 4 of 6	ENST00000526995.6	NP_004611.1
TRAF6	NM_145803.3	c.607-559A>G		intron_variant	Intron 5 of 7		NP_665802.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAF6	ENST00000526995.6	c.607-559A>G		intron_variant	Intron 4 of 6	1	NM_004620.4	ENSP00000433623.1
TRAF6	ENST00000348124.5	c.607-559A>G		intron_variant	Intron 5 of 7	1		ENSP00000337853.5
TRAF6	ENST00000529150.1	n.152-559A>G		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes AF: 0.0282 AC: 4278 AN: 151802 Hom.: 204 Cov.: 32

Gnomad AFR AF: 0.0959

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00926

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000971

Gnomad OTH AF: 0.0206

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

GnomAD4 genome AF: 0.0283 AC: 4298 AN: 151920 Hom.: 206 Cov.: 32 AF XY: 0.0280 AC XY: 2076 AN XY: 74270

African (AFR) AF: 0.0961 AC: 3981 AN: 41438

American (AMR) AF: 0.00919 AC: 140 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00194 AC: 10 AN: 5156

South Asian (SAS) AF: 0.0110 AC: 53 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

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

European-Non Finnish (NFE) AF: 0.000971 AC: 66 AN: 67938

Other (OTH) AF: 0.0204 AC: 43 AN: 2106

Alfa AF: 0.0191 Hom.: 11

Bravo AF: 0.0313

Asia WGS AF: 0.0140 AC: 50 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.9
DANN	Benign	0.78
PhyloP100		0.0010
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: rs5030461; hg19: chr11-36517156;