1-209762531-C-T

Variant names:

• chr1-209762531-C-T
• rs1246538247
• NM_025228.4:c.362C>T

Variant summary

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

The NM_025228.4(TRAF3IP3):​c.362C>T​(p.Ser121Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000758 in 1,319,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. S121Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: TRAF3IP3 NM_025228.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.126
• Publications: 0 publications found

Genes affected

TRAF3IP3 (HGNC:30766): (TRAF3 interacting protein 3) The gene encodes a protein that mediates cell growth by modulating the c-Jun N-terminal kinase signal transduction pathway. The encoded protein may also interact with a large multi-protein assembly containing the phosphatase 2A catalytic subunit. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

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=0.09895107).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025228.4. 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
	TRAF3IP3	NM_025228.4	MANE Select	c.362C>T	p.Ser121Phe	missense	Exon 4 of 17	NP_079504.2	Q9Y228-1
	TRAF3IP3	NM_001320143.2		c.362C>T	p.Ser121Phe	missense	Exon 4 of 17	NP_001307072.1	Q9Y228-1
	TRAF3IP3	NM_001320144.2		c.302C>T	p.Ser101Phe	missense	Exon 4 of 17	NP_001307073.1	Q9Y228-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAF3IP3	ENST00000367025.8	TSL:1 MANE Select	c.362C>T	p.Ser121Phe	missense	Exon 4 of 17	ENSP00000355992.3	Q9Y228-1
	TRAF3IP3	ENST00000367026.7	TSL:1	c.302C>T	p.Ser101Phe	missense	Exon 4 of 17	ENSP00000355993.3	Q9Y228-2
	TRAF3IP3	ENST00000478359.5	TSL:1	n.362C>T		non_coding_transcript_exon	Exon 4 of 13	ENSP00000417665.1	Q9Y228-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.58e-7 AC: 1 AN: 1319450 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 643780

African (AFR) AF: 0.00 AC: 0 AN: 27228

American (AMR) AF: 0.00 AC: 0 AN: 26124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19004

East Asian (EAS) AF: 0.00 AC: 0 AN: 37516

South Asian (SAS) AF: 0.00 AC: 0 AN: 60198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5174

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1042604

Other (OTH) AF: 0.0000186 AC: 1 AN: 53862

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.099	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.13
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.050
Sift	Uncertain	0.017	D
Sift4G	Benign	0.11	T
Polyphen		0.73	P
Vest4		0.24
MutPred		0.21		Loss of glycosylation at S121 (P = 0.0096)
MVP		0.38
MPC		0.14
ClinPred		0.32	T
GERP RS		0.14
Varity_R		0.11
gMVP		0.26
Mutation Taster		=92/8	polymorphism

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: rs1246538247; hg19: chr1-209935876; COSMIC: COSV50552072; COSMIC: COSV50552072;