Variant rs750055952 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015650.4(TRAF3IP1):c.1559T>G(p.Met520Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,457,804 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

TRAF3IP1
NM_015650.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 0.842

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRAF3IP1	NM_015650.4 link	c.1559T>G	p.Met520Arg	missense_variant	13/17	ENST00000373327.5	NP_056465.2	Q8TDR0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TRAF3IP1	ENST00000373327.5 link	c.1559T>G	p.Met520Arg	missense_variant	13/17	1	NM_015650.4	ENSP00000362424.4	Q8TDR0-1
TRAF3IP1	ENST00000391993.7 link	c.1361T>G	p.Met454Arg	missense_variant	11/15	1		ENSP00000375851.3	Q8TDR0-2
TRAF3IP1	ENST00000462122.1 link	n.570T>G		non_coding_transcript_exon_variant	4/7	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000816

AC:

AN:

245206

Hom.:

AF XY:

0.0000151

AC XY:

AN XY:

132288

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000606

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000412

AC:

AN:

1457804

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724982

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000458

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Senior-Loken syndrome 9

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 06, 2016

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 29, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects TRAF3IP1 function (PMID: 26487268). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 254147). This missense change has been observed in individual(s) with Senior-Loken syndrome (PMID: 26487268). This variant is present in population databases (rs750055952, ExAC 0.009%). This sequence change replaces methionine with arginine at codon 520 of the TRAF3IP1 protein (p.Met520Arg). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.42

CADD

Pathogenic

DANN

Uncertain

0.97

DEOGEN2

Benign

0.020

.;T

Eigen

Benign

0.050

Eigen_PC

Benign

-0.038

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.0076

MetaRNN

Uncertain

0.43

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.7

.;M

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.16

Sift

Benign

0.12

T;T

Sift4G

Benign

0.51

T;T

Polyphen

0.98

D;D

Vest4

0.52

MutPred

0.45

.;Gain of solvent accessibility (P = 0.0068);

MVP

0.36

MPC

0.66

ClinPred

0.80

GERP RS

3.7

Varity_R

0.45

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.98

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over