9-120913513-C-T

Position:

• chr9-120913513-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005658.5(TRAF1):​c.520G>A​(p.Glu174Lys) 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 1,461,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TRAF1 NM_005658.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.51

Genes affected

TRAF1 (HGNC:12031): (TNF receptor associated factor 1) The protein encoded by this gene is a member of the TNF receptor (TNFR) associated factor (TRAF) protein family. TRAF proteins associate with, and mediate the signal transduction from various receptors of the TNFR superfamily. This protein and TRAF2 form a heterodimeric complex, which is required for TNF-alpha-mediated activation of MAPK8/JNK and NF-kappaB. The protein complex formed by this protein and TRAF2 also interacts with inhibitor-of-apoptosis proteins (IAPs), and thus mediates the anti-apoptotic signals from TNF receptors. The expression of this protein can be induced by Epstein-Barr virus (EBV). EBV infection membrane protein 1 (LMP1) is found to interact with this and other TRAF proteins; this interaction is thought to link LMP1-mediated B lymphocyte transformation to the signal transduction from TNFR family receptors. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16282997).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRAF1	NM_005658.5	c.520G>A	p.Glu174Lys	missense_variant	5/8	ENST00000373887.8	NP_005649.1
TRAF1	NM_001190945.2	c.520G>A	p.Glu174Lys	missense_variant	6/9		NP_001177874.1
TRAF1	NM_001190947.2	c.154G>A	p.Glu52Lys	missense_variant	3/6		NP_001177876.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRAF1	ENST00000373887.8	c.520G>A	p.Glu174Lys	missense_variant	5/8	1	NM_005658.5	ENSP00000362994.3
TRAF1	ENST00000540010.1	c.520G>A	p.Glu174Lys	missense_variant	6/9	1		ENSP00000443183.1
TRAF1	ENST00000546084.5	c.154G>A	p.Glu52Lys	missense_variant	3/6	2		ENSP00000438583.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461684 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727146

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2024

The c.520G>A (p.E174K) alteration is located in exon 5 (coding exon 4) of the TRAF1 gene. This alteration results from a G to A substitution at nucleotide position 520, causing the glutamic acid (E) at amino acid position 174 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.045	.;T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.038
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T;.;T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	.;L;L
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.81	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.30	T;T;T
Sift4G	Benign	0.60	T;T;T
Polyphen		0.0050	.;B;B
Vest4		0.25
MutPred		0.40		.;Gain of ubiquitination at E174 (P = 0.0082);Gain of ubiquitination at E174 (P = 0.0082);
MVP		0.57
MPC		0.29
ClinPred		0.65	D
GERP RS		5.3
Varity_R		0.15
gMVP		0.34

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-123675791;