2-238320688-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_015650.4(TRAF3IP1):​c.26C>T​(p.Thr9Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000141 in 1,417,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T9R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 7.9e-7 ( 0 hom. )

Consequence

TRAF3IP1
NM_015650.4 missense

Scores

9
7
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.27
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.835

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TRAF3IP1NM_015650.4 linkc.26C>T p.Thr9Met missense_variant Exon 1 of 17 ENST00000373327.5 NP_056465.2 Q8TDR0-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TRAF3IP1ENST00000373327.5 linkc.26C>T p.Thr9Met missense_variant Exon 1 of 17 1 NM_015650.4 ENSP00000362424.4 Q8TDR0-1
TRAF3IP1ENST00000391993.7 linkc.26C>T p.Thr9Met missense_variant Exon 1 of 15 1 ENSP00000375851.3 Q8TDR0-2
TRAF3IP1ENST00000409739.2 linkn.26C>T non_coding_transcript_exon_variant Exon 1 of 5 3 ENSP00000386648.2 H7BZ10

Frequencies

GnomAD3 genomes
AF:
0.00000662
AC:
1
AN:
151086
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000148
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
7.90e-7
AC:
1
AN:
1266290
Hom.:
0
Cov.:
30
AF XY:
0.00000160
AC XY:
1
AN XY:
624546
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
9.96e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000662
AC:
1
AN:
151086
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
73768
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000148
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Apr 18, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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 missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with TRAF3IP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 9 of the TRAF3IP1 protein (p.Thr9Met). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.12
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.30
.;T
Eigen
Uncertain
0.67
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.89
D;D
M_CAP
Pathogenic
0.58
D
MetaRNN
Pathogenic
0.83
D;D
MetaSVM
Benign
-0.45
T
MutationAssessor
Pathogenic
3.3
M;M
PrimateAI
Pathogenic
0.93
D
PROVEAN
Pathogenic
-4.5
D;D
REVEL
Uncertain
0.52
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.73
MutPred
0.52
Loss of phosphorylation at T9 (P = 0.0183);Loss of phosphorylation at T9 (P = 0.0183);
MVP
0.53
MPC
0.54
ClinPred
1.0
D
GERP RS
3.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.79
gMVP
0.81

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

LitVar

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

Other links and lift over

dbSNP: rs1214100414; hg19: chr2-239229329; API