2-238333959-G-C
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_015650.4(TRAF3IP1):c.988-1G>C variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0000175 in 1,602,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )
Consequence
TRAF3IP1
NM_015650.4 splice_acceptor
NM_015650.4 splice_acceptor
Scores
2
4
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 5.17
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 Pathogenic. Variant got 22 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 2-238333959-G-C is Pathogenic according to our data. Variant chr2-238333959-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRAF3IP1 | NM_015650.4 | c.988-1G>C | splice_acceptor_variant | ENST00000373327.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRAF3IP1 | ENST00000373327.5 | c.988-1G>C | splice_acceptor_variant | 1 | NM_015650.4 | ||||
TRAF3IP1 | ENST00000391993.7 | c.988-1G>C | splice_acceptor_variant | 1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152008Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
2
AN:
152008
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00000421 AC: 1AN: 237516Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 128026
GnomAD3 exomes
AF:
AC:
1
AN:
237516
Hom.:
AF XY:
AC XY:
0
AN XY:
128026
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000179 AC: 26AN: 1450826Hom.: 0 Cov.: 31 AF XY: 0.0000222 AC XY: 16AN XY: 720882
GnomAD4 exome
AF:
AC:
26
AN:
1450826
Hom.:
Cov.:
31
AF XY:
AC XY:
16
AN XY:
720882
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152008Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74226
GnomAD4 genome
?
AF:
AC:
2
AN:
152008
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
74226
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
1
ExAC
?
AF:
AC:
1
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Short-rib thoracic dysplasia 6 with or without polydactyly Pathogenic:2
Pathogenic, no assertion criteria provided | research | Dan Cohn Lab, University Of California Los Angeles | Jun 01, 2017 | - - |
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
TRAF3IP1-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 13, 2023 | The TRAF3IP1 c.988-1G>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported in an individual with short rib-polydactyly syndrome, type 2 (Zhang et al. 2018. PubMed ID: 29068549). This variant is reported in 0.00094% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-239242600-G-C). Variants that disrupt the consensus splice acceptor site in TRAF3IP1 are expected to be pathogenic. This variant is interpreted as likely pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 05, 2022 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 446656). Disruption of this splice site has been observed in individual(s) with short-rib polydactyly syndrome (PMID: 29068549). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects an acceptor splice site in intron 6 of the TRAF3IP1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TRAF3IP1 are known to be pathogenic (PMID: 21945076, 26487268, 29068549). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 7
DS_AL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at