Genetic Variant TRAF3IP3:p.Arg164His (chr1-209762660-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_025228.4(TRAF3IP3):c.491G>A(p.Arg164His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000327 in 1,344,914 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. 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. R164P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 19)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

TRAF3IP3
NM_025228.4 missense, splice_region

Scores

Splicing: ADA: 0.00005232

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.315

Publications

0 publications found

Variant links:

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]

TRAF3IP3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.045075208).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRAF3IP3	NM_025228.4	MANE Select	c.491G>A	p.Arg164His	missense splice_region	Exon 4 of 17	NP_079504.2	Q9Y228-1
TRAF3IP3	NM_001320143.2		c.491G>A	p.Arg164His	missense splice_region	Exon 4 of 17	NP_001307072.1	Q9Y228-1
TRAF3IP3	NM_001320144.2		c.431G>A	p.Arg144His	missense splice_region	Exon 4 of 17	NP_001307073.1	Q9Y228-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRAF3IP3	ENST00000367025.8	TSL:1 MANE Select	c.491G>A	p.Arg164His	missense splice_region	Exon 4 of 17	ENSP00000355992.3	Q9Y228-1
TRAF3IP3	ENST00000367026.7	TSL:1	c.431G>A	p.Arg144His	missense splice_region	Exon 4 of 17	ENSP00000355993.3	Q9Y228-2
TRAF3IP3	ENST00000478359.5	TSL:1	n.491G>A		splice_region non_coding_transcript_exon	Exon 4 of 13	ENSP00000417665.1	Q9Y228-3

Frequencies

GnomAD3 genomes

AF:

0.0000659

AC:

AN:

75896

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000304

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:

0.0000694

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000110

AC:

AN:

181256

AF XY:

0.0000103

show subpopulations

Gnomad AFR exome

AF:

0.0000925

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:

0.0000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000307

AC:

AN:

1268990

Hom.:

Cov.:

AF XY:

0.0000386

AC XY:

AN XY:

621586

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21488

American (AMR)

AF:

0.00

AC:

AN:

30638

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18946

East Asian (EAS)

AF:

0.00

AC:

AN:

32996

South Asian (SAS)

AF:

0.0000166

AC:

AN:

60142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40790

Middle Eastern (MID)

AF:

0.000201

AC:

AN:

4964

European-Non Finnish (NFE)

AF:

0.0000367

AC:

AN:

1009524

Other (OTH)

AF:

0.00

AC:

AN:

49502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000659

AC:

AN:

75924

Hom.:

Cov.:

AF XY:

0.0000265

AC XY:

AN XY:

37766

show subpopulations

African (AFR)

AF:

0.000302

AC:

AN:

6624

American (AMR)

AF:

0.00

AC:

AN:

9264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2394

East Asian (EAS)

AF:

0.00

AC:

AN:

3478

South Asian (SAS)

AF:

0.00

AC:

AN:

2942

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6122

Middle Eastern (MID)

AF:

0.00

AC:

AN:

180

European-Non Finnish (NFE)

AF:

0.0000694

AC:

AN:

43230

Other (OTH)

AF:

0.00

AC:

AN:

1110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.018

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.77

M_CAP

Benign

0.0070

MetaRNN

Benign

0.045

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.3

PhyloP100

0.32

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.7

REVEL

Benign

0.040

Sift

Uncertain

0.010

Sift4G

Uncertain

0.023

Polyphen

0.97

Vest4

0.28

MutPred

0.23

Gain of ubiquitination at K161 (P = 0.0261)

MVP

0.38

MPC

0.17

ClinPred

0.10

GERP RS

-0.78

Varity_R

0.066

gMVP

0.22

Mutation Taster

=79/21

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000052

dbscSNV1_RF

Benign

0.23

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over