chr9-120913681-G-C

Position:

• chr9-120913681-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005658.5(TRAF1):​c.352C>G​(p.Leu118Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRAF1 NM_005658.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.72

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39355087).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAF1	NM_005658.5	c.352C>G	p.Leu118Val	missense_variant	5/8	ENST00000373887.8
TRAF1	NM_001190945.2	c.352C>G	p.Leu118Val	missense_variant	6/9
TRAF1	NM_001190947.2	c.-15C>G		5_prime_UTR_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAF1	ENST00000373887.8	c.352C>G	p.Leu118Val	missense_variant	5/8	1	NM_005658.5	P1
TRAF1	ENST00000540010.1	c.352C>G	p.Leu118Val	missense_variant	6/9	1		P1
TRAF1	ENST00000546084.5	c.-15C>G		5_prime_UTR_variant	3/6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Feb 28, 2023

The c.352C>G (p.L118V) alteration is located in exon 5 (coding exon 4) of the TRAF1 gene. This alteration results from a C to G substitution at nucleotide position 352, causing the leucine (L) at amino acid position 118 to be replaced by a valine (V). 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	0.13
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.72	.;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.39	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Pathogenic	3.2	M;M
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.11
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		0.35	B;B
Vest4		0.37
MutPred		0.43		Gain of MoRF binding (P = 0.0803);Gain of MoRF binding (P = 0.0803);
MVP		0.59
MPC		0.32
ClinPred		0.89	D
GERP RS		3.5
Varity_R		0.17
gMVP		0.44

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: chr9-123675959;