9-120913669-A-G

Variant names:

• chr9-120913669-A-G
• rs144102454
• NM_005658.5:c.364T>C

Variant summary

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

The NM_005658.5(TRAF1):​c.364T>C​(p.Phe122Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000263 in 151,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000026 (0 hom., cov: 32)
• Consequence: TRAF1 NM_005658.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.853
• Publications: 0 publications found

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

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=0.099758744).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAF1	NM_005658.5	c.364T>C	p.Phe122Leu	missense_variant	Exon 5 of 8	ENST00000373887.8	NP_005649.1
TRAF1	NM_001190945.2	c.364T>C	p.Phe122Leu	missense_variant	Exon 6 of 9		NP_001177874.1
TRAF1	NM_001190947.2	c.-3T>C		5_prime_UTR_variant	Exon 3 of 6		NP_001177876.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAF1	ENST00000373887.8	c.364T>C	p.Phe122Leu	missense_variant	Exon 5 of 8	1	NM_005658.5	ENSP00000362994.3
TRAF1	ENST00000540010.1	c.364T>C	p.Phe122Leu	missense_variant	Exon 6 of 9	1		ENSP00000443183.1
TRAF1	ENST00000546084.5	c.-3T>C		5_prime_UTR_variant	Exon 3 of 6	2		ENSP00000438583.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151934 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249562 AF XY: 0.00

Gnomad AFR exome AF: 0.0000632

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151934 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74186

African (AFR) AF: 0.0000967 AC: 4 AN: 41344

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.364T>C (p.F122L) alteration is located in exon 5 (coding exon 4) of the TRAF1 gene. This alteration results from a T to C substitution at nucleotide position 364, causing the phenylalanine (F) at amino acid position 122 to be replaced by a leucine (L). 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	Uncertain	0.43
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	15
DANN	Benign	0.74
DEOGEN2	Benign	0.050	T;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.51	.;T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L
PhyloP100		0.85
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.37	N;N
REVEL	Benign	0.071
Sift	Benign	0.56	T;T
Sift4G	Benign	0.71	T;T
Polyphen		0.0	B;B
Vest4		0.065
MutPred		0.71		Gain of MoRF binding (P = 0.1336);Gain of MoRF binding (P = 0.1336);
MVP		0.37
MPC		0.25
ClinPred		0.098	T
GERP RS		-0.34
Varity_R		0.031
gMVP		0.27
Mutation Taster		=93/7	polymorphism

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: rs144102454; hg19: chr9-123675947;