NM_015650.4:c.416G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015650.4(TRAF3IP1):c.416G>A(p.Arg139Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0339 in 1,613,950 control chromosomes in the GnomAD database, including 1,053 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R139W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.024 ( 58 hom., cov: 32)

Exomes 𝑓: 0.035 ( 995 hom. )

Consequence

TRAF3IP1
NM_015650.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.43

Publications

9 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=0.001930654).

BP6

Variant 2-238328747-G-A is Benign according to our data. Variant chr2-238328747-G-A is described in ClinVar as Benign. ClinVar VariationId is 1167927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0238 (3618/152108) while in subpopulation NFE AF = 0.0374 (2542/67996). AF 95% confidence interval is 0.0362. There are 58 homozygotes in GnomAd4. There are 1646 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 58 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015650.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAF3IP1	NM_015650.4	MANE Select	c.416G>A	p.Arg139Gln	missense	Exon 4 of 17	NP_056465.2
	TRAF3IP1	NM_001139490.1		c.416G>A	p.Arg139Gln	missense	Exon 4 of 15	NP_001132962.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TRAF3IP1	ENST00000373327.5	TSL:1 MANE Select	c.416G>A	p.Arg139Gln	missense	Exon 4 of 17	ENSP00000362424.4
TRAF3IP1	ENST00000391993.7	TSL:1	c.416G>A	p.Arg139Gln	missense	Exon 4 of 15	ENSP00000375851.3
TRAF3IP1	ENST00000935943.1		c.416G>A	p.Arg139Gln	missense	Exon 4 of 16	ENSP00000606002.1

Frequencies

GnomAD3 genomes

AF:

0.0238

AC:

3619

AN:

151990

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00687

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0201

Gnomad ASJ

AF:

0.0377

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0245

Gnomad FIN

AF:

0.0148

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0374

Gnomad OTH

AF:

0.0249

GnomAD2 exomes

AF:

0.0260

AC:

6525

AN:

251372

AF XY:

0.0265

show subpopulations

Gnomad AFR exome

AF:

0.00665

Gnomad AMR exome

AF:

0.0165

Gnomad ASJ exome

AF:

0.0373

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0160

Gnomad NFE exome

AF:

0.0363

Gnomad OTH exome

AF:

0.0285

GnomAD4 exome

AF:

0.0349

AC:

51046

AN:

1461842

Hom.:

995

Cov.:

AF XY:

0.0348

AC XY:

25284

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00559

AC:

187

AN:

33480

American (AMR)

AF:

0.0173

AC:

773

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0368

AC:

961

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0265

AC:

2290

AN:

86254

European-Finnish (FIN)

AF:

0.0156

AC:

834

AN:

53420

Middle Eastern (MID)

AF:

0.0338

AC:

195

AN:

5768

European-Non Finnish (NFE)

AF:

0.0394

AC:

43846

AN:

1111974

Other (OTH)

AF:

0.0324

AC:

1959

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

2598

5196

7793

10391

12989

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1662

3324

4986

6648

8310

<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:

0.0238

AC:

3618

AN:

152108

Hom.:

Cov.:

AF XY:

0.0221

AC XY:

1646

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00685

AC:

284

AN:

41486

American (AMR)

AF:

0.0200

AC:

306

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0377

AC:

131

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.0251

AC:

121

AN:

4816

European-Finnish (FIN)

AF:

0.0148

AC:

156

AN:

10574

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0374

AC:

2542

AN:

67996

Other (OTH)

AF:

0.0246

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

189

378

567

756

945

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.0323

Hom.:

211

Bravo

AF:

0.0237

TwinsUK

AF:

0.0399

AC:

148

ALSPAC

AF:

0.0410

AC:

158

ESP6500AA

AF:

0.00840

AC:

ESP6500EA

AF:

0.0399

AC:

343

ExAC

AF:

0.0249

AC:

3028

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

TRAF3IP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0097

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0019

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

2.4

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.1

REVEL

Benign

0.091

Sift

Benign

0.062

Sift4G

Uncertain

0.030

Polyphen

0.086

Vest4

0.15

MPC

0.39

ClinPred

0.018

GERP RS

0.17

Varity_R

0.030

gMVP

0.16

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over