11-36490432-C-T

Variant names:

• chr11-36490432-C-T
• rs145275891
• NM_004620.4:c.975G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004620.4(TRAF6):​c.975G>A​(p.Met325Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TRAF6 NM_004620.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.58
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1543453).

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.975G>A	p.Met325Ile	missense	Exon 7 of 7	NP_004611.1	Q9Y4K3
	TRAF6	NM_145803.3		c.975G>A	p.Met325Ile	missense	Exon 8 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.975G>A	p.Met325Ile	missense	Exon 7 of 7	ENSP00000433623.1	Q9Y4K3
	TRAF6	ENST00000348124.5	TSL:1	c.975G>A	p.Met325Ile	missense	Exon 8 of 8	ENSP00000337853.5	Q9Y4K3
	TRAF6	ENST00000876418.1		c.969G>A	p.Met323Ile	missense	Exon 7 of 7	ENSP00000546477.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461616 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727104

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5530

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.082
DANN	Benign	0.69
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.41	N
PhyloP100		-1.6
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.19
Sift	Benign	0.21	T
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.062
MutPred		0.41		Loss of disorder (P = 0.0604)
MVP		0.36
MPC		0.74
ClinPred		0.019	T
GERP RS		-0.036
Varity_R		0.031
gMVP		0.27
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs145275891; hg19: chr11-36511982;