rs146832696

Variant names:

• chr11-36495046-A-G
• rs146832696
• NM_004620.4:c.608T>C

Your query was ambiguous. Multiple possible variants found:

• chr11-36495046-A-G
• chr11-36495046-A-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004620.4(TRAF6):​c.608T>C​(p.Ile203Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,598,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I203M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: TRAF6 NM_004620.4 missense, splice_region
• Scores: Splicing: ADA: 0.0002879
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.44
• Publications: 2 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15294707).
• BS2: High AC in GnomAd4 at 10 AD gene.

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.608T>C	p.Ile203Thr	missense splice_region	Exon 5 of 7	NP_004611.1	Q9Y4K3
	TRAF6	NM_145803.3		c.608T>C	p.Ile203Thr	missense splice_region	Exon 6 of 8	NP_665802.1	Q9Y4K3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAF6	ENST00000526995.6	TSL:1 MANE Select	c.608T>C	p.Ile203Thr	missense splice_region	Exon 5 of 7	ENSP00000433623.1	Q9Y4K3
	TRAF6	ENST00000348124.5	TSL:1	c.608T>C	p.Ile203Thr	missense splice_region	Exon 6 of 8	ENSP00000337853.5	Q9Y4K3
	TRAF6	ENST00000876418.1		c.608T>C	p.Ile203Thr	missense splice_region	Exon 5 of 7	ENSP00000546477.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000563 AC: 14 AN: 248846 AF XY: 0.0000668

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000181 AC: 262 AN: 1446188 Hom.: 0 Cov.: 26 AF XY: 0.000192 AC XY: 138 AN XY: 720442

African (AFR) AF: 0.00 AC: 0 AN: 33050

American (AMR) AF: 0.0000905 AC: 4 AN: 44216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25932

East Asian (EAS) AF: 0.00 AC: 0 AN: 39406

South Asian (SAS) AF: 0.00 AC: 0 AN: 85324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.000231 AC: 254 AN: 1099536

Other (OTH) AF: 0.0000669 AC: 4 AN: 59790

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41470

American (AMR) AF: 0.000131 AC: 2 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5208

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000115 Hom.: 0

Bravo AF: 0.0000680

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Benign	0.63
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.4
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.029
Sift	Benign	0.63	T
Sift4G	Benign	0.46	T
Polyphen		0.0020	B
Vest4		0.26
MVP		0.50
MPC		0.86
ClinPred		0.064	T
GERP RS		3.1
Varity_R		0.13
gMVP		0.42
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00029
dbscSNV1_RF	Benign	0.042
SpliceAI score (max)		0.12		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: rs146832696; hg19: chr11-36516596;