1-209762660-G-T

Variant names:

• chr1-209762660-G-T
• rs532039513
• NM_025228.4:c.491G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_025228.4(TRAF3IP3):​c.491G>T​(p.Arg164Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000669 in 1,344,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R164P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 19)
  • Exomes 𝑓: 0.0000047 (0 hom.)
• Consequence: TRAF3IP3 NM_025228.4 missense, splice_region
• Scores: Splicing: ADA: 0.00003611
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.315
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060400426).

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.491G>T	p.Arg164Leu	missense splice_region	Exon 4 of 17	NP_079504.2	Q9Y228-1
	TRAF3IP3	NM_001320143.2		c.491G>T	p.Arg164Leu	missense splice_region	Exon 4 of 17	NP_001307072.1	Q9Y228-1
	TRAF3IP3	NM_001320144.2		c.431G>T	p.Arg144Leu	missense splice_region	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.491G>T	p.Arg164Leu	missense splice_region	Exon 4 of 17	ENSP00000355992.3	Q9Y228-1
	TRAF3IP3	ENST00000367026.7	TSL:1	c.431G>T	p.Arg144Leu	missense splice_region	Exon 4 of 17	ENSP00000355993.3	Q9Y228-2
	TRAF3IP3	ENST00000478359.5	TSL:1	n.491G>T		splice_region non_coding_transcript_exon	Exon 4 of 13	ENSP00000417665.1	Q9Y228-3

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 3 AN: 75896 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000324

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

GnomAD4 exome AF: 0.00000473 AC: 6 AN: 1268990 Hom.: 0 Cov.: 32 AF XY: 0.00000483 AC XY: 3 AN XY: 621586

African (AFR) AF: 0.00 AC: 0 AN: 21488

American (AMR) AF: 0.000131 AC: 4 AN: 30638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18946

East Asian (EAS) AF: 0.00 AC: 0 AN: 32996

South Asian (SAS) AF: 0.00 AC: 0 AN: 60142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40790

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4964

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1009524

Other (OTH) AF: 0.0000404 AC: 2 AN: 49502

GnomAD4 genome AF: 0.0000395 AC: 3 AN: 75896 Hom.: 0 Cov.: 19 AF XY: 0.0000265 AC XY: 1 AN XY: 37726

African (AFR) AF: 0.00 AC: 0 AN: 6588

American (AMR) AF: 0.000324 AC: 3 AN: 9256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2394

East Asian (EAS) AF: 0.00 AC: 0 AN: 3484

South Asian (SAS) AF: 0.00 AC: 0 AN: 2942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 192

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 43236

Other (OTH) AF: 0.00 AC: 0 AN: 1102

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.00000827 AC: 1

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	Benign	0.15
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.32
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.037
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.030	D
Polyphen		0.29	B
Vest4		0.28
MutPred		0.29		Gain of ubiquitination at K161 (P = 0.0317)
MVP		0.24
MPC		0.29
ClinPred		0.49	T
GERP RS		-0.78
Varity_R		0.12
gMVP		0.31
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000036
dbscSNV1_RF	Benign	0.064
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: rs532039513; hg19: chr1-209936005;