NM_004295.4:c.341C>T

Variant names:

• chr17-28748057-C-T
• rs996953187
• NM_004295.4:c.341C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM2 PP3_Moderate BS2

The NM_004295.4(TRAF4):​c.341C>T​(p.Pro114Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TRAF4 NM_004295.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.64
• Publications: 0 publications found

Genes affected

TRAF4 (HGNC:12034): (TNF receptor associated factor 4) This gene encodes a member of the TNF receptor associated factor (TRAF) family. TRAF proteins are associated with, and mediate signal transduction from members of the TNF receptor superfamily. The encoded protein has been shown to interact with neurotrophin receptor, p75 (NTR/NTSR1), and negatively regulate NTR induced cell death and NF-kappa B activation. This protein has been found to bind to p47phox, a cytosolic regulatory factor included in a multi-protein complex known as NAD(P)H oxidase. This protein thus, is thought to be involved in the oxidative activation of MAPK8/JNK. Alternatively spliced transcript variants have been observed but the full-length nature of only one has been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004295.4. 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
	TRAF4	NM_004295.4	MANE Select	c.341C>T	p.Pro114Leu	missense	Exon 4 of 7	NP_004286.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAF4	ENST00000262395.10	TSL:1 MANE Select	c.341C>T	p.Pro114Leu	missense	Exon 4 of 7	ENSP00000262395.5	Q9BUZ4-1
	TRAF4	ENST00000262396.10	TSL:1	c.341C>T	p.Pro114Leu	missense	Exon 4 of 5	ENSP00000262396.6	A0A0C4DFM9
	TRAF4	ENST00000444415.7	TSL:5	c.341C>T	p.Pro114Leu	missense	Exon 4 of 8	ENSP00000438154.2	F6SA91

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461772 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727176

African (AFR) AF: 0.00 AC: 0 AN: 33480

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: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

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	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.33	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.53
MutPred		0.68		Loss of disorder (P = 0.0267)
MVP		0.72
MPC		1.6
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.27
gMVP		0.73
Mutation Taster		=11/89	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs996953187; hg19: chr17-27075075;