chr2-238397627-A-C

Variant names:

Variant summary

Our verdict is . The variant received -14 classification points (ACMG Germline Pathogenicity v2019): 0P and 14B. BA1BP4_ModerateBP6_Strong

The NM_015650.4(TRAF3IP1):c.1858A>C (p.Met620Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0759 (AC=122,042) in the gnomAD database across 1,607,770 control chromosomes, including 5,344 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.083. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.M620I: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 833894); p.M620L: Uncertain_significance (ClinVar VariationId 1002358, 1 star); p.M620L: Likely_benign (ClinVar VariationId 3010811, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

Frequency

Genomes: 𝑓 0.062 ( 386 hom., cov: 32)

Exomes 𝑓: 0.077 ( 4958 hom. )

Consequence

TRAF3IP1
NM_015650.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.126

Publications

45 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):

ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Senior-Loken syndrome 9
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, 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

new If you want to explore the variant's impact on the transcript NM_015650.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -14 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

BP6

ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.0830 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAF3IP1	NM_015650.4	MANE Select	c.1858A>C	p.Met620Leu	missense	Exon 16 of 17	NP_056465.2
	TRAF3IP1	NM_001139490.1		c.1660A>C	p.Met554Leu	missense	Exon 14 of 15	NP_001132962.1	Q8TDR0-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRAF3IP1	ENST00000373327.5	TSL:1 MANE Select	c.1858A>C	p.Met620Leu	missense	Exon 16 of 17	ENSP00000362424.4	Q8TDR0-1
TRAF3IP1	ENST00000391993.7	TSL:1	c.1660A>C	p.Met554Leu	missense	Exon 14 of 15	ENSP00000375851.3	Q8TDR0-2
TRAF3IP1	ENST00000935943.1		c.1762A>C	p.Met588Leu	missense	Exon 15 of 16	ENSP00000606002.1

Frequencies

GnomAD3 genomes

AF:

0.0615

AC:

9313

AN:

151342

Hom.:

384

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0237

Gnomad AMI

AF:

0.0264

Gnomad AMR

AF:

0.0416

Gnomad ASJ

AF:

0.0479

Gnomad EAS

AF:

0.0457

Gnomad SAS

AF:

0.0453

Gnomad FIN

AF:

0.141

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0805

Gnomad OTH

AF:

0.0551

GnomAD2 exomes

AF:

0.0635

AC:

15763

AN:

248156

AF XY:

0.0645

show subpopulations

Gnomad AFR exome

AF:

0.0198

Gnomad AMR exome

AF:

0.0262

Gnomad ASJ exome

AF:

0.0415

Gnomad EAS exome

AF:

0.0385

Gnomad FIN exome

AF:

0.141

Gnomad NFE exome

AF:

0.0790

Gnomad OTH exome

AF:

0.0617

GnomAD4 exome

AF:

0.0774

AC:

112720

AN:

1456310

Hom.:

4958

Cov.:

AF XY:

0.0763

AC XY:

55314

AN XY:

724508

show subpopulations

African (AFR)

AF:

0.0212

AC:

707

AN:

33406

American (AMR)

AF:

0.0306

AC:

1368

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.0503

AC:

1314

AN:

26100

East Asian (EAS)

AF:

0.0321

AC:

1272

AN:

39668

South Asian (SAS)

AF:

0.0422

AC:

3633

AN:

86182

European-Finnish (FIN)

AF:

0.147

AC:

7643

AN:

52092

Middle Eastern (MID)

AF:

0.0200

AC:

115

AN:

5760

European-Non Finnish (NFE)

AF:

0.0835

AC:

92523

AN:

1108224

Other (OTH)

AF:

0.0688

AC:

4145

AN:

60210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

6383

12765

19148

25530

31913

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3370

6740

10110

13480

16850

<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:

0.0615

AC:

9322

AN:

151460

Hom.:

386

Cov.:

AF XY:

0.0625

AC XY:

4626

AN XY:

74008

show subpopulations

African (AFR)

AF:

0.0238

AC:

984

AN:

41356

American (AMR)

AF:

0.0416

AC:

633

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.0479

AC:

166

AN:

3466

East Asian (EAS)

AF:

0.0456

AC:

234

AN:

5128

South Asian (SAS)

AF:

0.0455

AC:

216

AN:

4746

European-Finnish (FIN)

AF:

0.141

AC:

1484

AN:

10496

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0806

AC:

5456

AN:

67734

Other (OTH)

AF:

0.0560

AC:

118

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

428

856

1285

1713

2141

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

208

312

416

520

<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:

0.0697

Hom.:

1718

Bravo

AF:

0.0528

Asia WGS

AF:

0.0370

AC:

127

AN:

3418

EpiCase

AF:

0.0712

EpiControl

AF:

0.0733

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.0204

AC:

2357

AN:

115806

Turkish Variome

AF:

0.0264

AC:

175

AN:

6634

Hom.:

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.0440

AC:

394

AN:

8960

Hom.:

ABraOM SABE-WGS-1171

AF:

0.0538

AC:

126

AN:

2340

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.81

CADD

Benign

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.0070

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.25

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.8

PhyloP100

0.13

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.49

REVEL

Benign

0.052

Sift

Benign

1.0

Sift4G

Benign

1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.038

gMVP

0.048

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over