2-238329110-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015650.4(TRAF3IP1):c.683A>G(p.Asn228Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0601 in 1,550,390 control chromosomes in the GnomAD database, including 5,130 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. N228N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.12 ( 1737 hom., cov: 31)

Exomes 𝑓: 0.054 ( 3393 hom. )

Consequence

TRAF3IP1
NM_015650.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.658

Publications

10 publications found

Variant links:

Genes affected

TRAF3IP1 (HGNC:17861): (TRAF3 interacting protein 1) The protein encoded by this gene interacts with TNF receptor-associated factor 3, tethering it to cytoskeletal microtubules. The encoded protein is also an inhibitor of the innate type I IFN response. Defects in this gene are a cause of Senior-Loken syndrome 9. [provided by RefSeq, Mar 2017]

TRAF3IP1 Gene-Disease associations (from GenCC):

Senior-Loken syndrome 9
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Senior-Loken syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
short rib-polydactyly syndrome, Majewski type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TRAF3IP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0046848953).

BP6

Variant 2-238329110-A-G is Benign according to our data. Variant chr2-238329110-A-G is described in ClinVar as Benign. ClinVar VariationId is 1167549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAF3IP1	NM_015650.4 link	c.683A>G	p.Asn228Ser	missense_variant	Exon 5 of 17	ENST00000373327.5	NP_056465.2	Q8TDR0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TRAF3IP1	ENST00000373327.5 link	c.683A>G	p.Asn228Ser	missense_variant	Exon 5 of 17	1	NM_015650.4	ENSP00000362424.4	Q8TDR0-1
TRAF3IP1	ENST00000391993.7 link	c.683A>G	p.Asn228Ser	missense_variant	Exon 5 of 15	1		ENSP00000375851.3	Q8TDR0-2
TRAF3IP1	ENST00000409739.2 link	n.*552A>G		non_coding_transcript_exon_variant	Exon 5 of 5	3		ENSP00000386648.2	H7BZ10
TRAF3IP1	ENST00000409739.2 link	n.*552A>G		3_prime_UTR_variant	Exon 5 of 5	3		ENSP00000386648.2	H7BZ10

Frequencies

GnomAD3 genomes

AF:

0.116

AC:

17578

AN:

151526

Hom.:

1732

Cov.:

show subpopulations

Gnomad AFR

AF:

0.267

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0814

Gnomad ASJ

AF:

0.0473

Gnomad EAS

AF:

0.103

Gnomad SAS

AF:

0.113

Gnomad FIN

AF:

0.113

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0394

Gnomad OTH

AF:

0.0982

GnomAD2 exomes

AF:

0.0810

AC:

12466

AN:

153818

AF XY:

0.0782

show subpopulations

Gnomad AFR exome

AF:

0.270

Gnomad AMR exome

AF:

0.0759

Gnomad ASJ exome

AF:

0.0467

Gnomad EAS exome

AF:

0.108

Gnomad FIN exome

AF:

0.105

Gnomad NFE exome

AF:

0.0409

Gnomad OTH exome

AF:

0.0702

GnomAD4 exome

AF:

0.0541

AC:

75608

AN:

1398746

Hom.:

3393

Cov.:

AF XY:

0.0546

AC XY:

37684

AN XY:

690062

show subpopulations

African (AFR)

AF:

0.280

AC:

8795

AN:

31398

American (AMR)

AF:

0.0768

AC:

2722

AN:

35426

Ashkenazi Jewish (ASJ)

AF:

0.0451

AC:

1135

AN:

25142

East Asian (EAS)

AF:

0.112

AC:

3994

AN:

35738

South Asian (SAS)

AF:

0.0985

AC:

7802

AN:

79196

European-Finnish (FIN)

AF:

0.103

AC:

5089

AN:

49306

Middle Eastern (MID)

AF:

0.0991

AC:

559

AN:

5642

European-Non Finnish (NFE)

AF:

0.0386

AC:

41610

AN:

1078916

Other (OTH)

AF:

0.0673

AC:

3902

AN:

57982

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

4170

8339

12509

16678

20848

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1766

3532

5298

7064

8830

<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:

0.116

AC:

17609

AN:

151644

Hom.:

1737

Cov.:

AF XY:

0.118

AC XY:

8773

AN XY:

74120

show subpopulations

African (AFR)

AF:

0.267

AC:

11019

AN:

41216

American (AMR)

AF:

0.0815

AC:

1243

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.0473

AC:

164

AN:

3468

East Asian (EAS)

AF:

0.102

AC:

526

AN:

5150

South Asian (SAS)

AF:

0.113

AC:

537

AN:

4770

European-Finnish (FIN)

AF:

0.113

AC:

1194

AN:

10532

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0394

AC:

2674

AN:

67944

Other (OTH)

AF:

0.0972

AC:

205

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

701

1403

2104

2806

3507

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

178

356

534

712

890

<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:

0.0683

Hom.:

1501

Bravo

AF:

0.120

TwinsUK

AF:

0.0345

AC:

128

ALSPAC

AF:

0.0418

AC:

161

ESP6500AA

AF:

0.234

AC:

975

ESP6500EA

AF:

0.0362

AC:

298

ExAC

AF:

0.0443

AC:

3961

Asia WGS

AF:

0.0980

AC:

341

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TRAF3IP1-related disorder

Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.81

CADD

Benign

2.2

(source)

DANN

Benign

0.24

DEOGEN2

Benign

0.0048

.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0012

LIST_S2

Benign

0.15

T;T

MetaRNN

Benign

0.0047

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.60

N;N

PhyloP100

0.66

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.060

N;N

REVEL

Benign

0.033

Sift

Benign

0.42

T;T

Sift4G

Benign

0.86

T;T

Polyphen

0.0

B;B

Vest4

0.026

MPC

0.11

ClinPred

0.0012

GERP RS

-0.82

Varity_R

0.013

gMVP

0.026

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over