rs199736345
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP3
The NM_004239.4(TRIP11):c.5719+2T>C variant causes a splice donor change. The variant allele was found at a frequency of 0.000235 in 1,607,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00025 ( 0 hom. )
Consequence
TRIP11
NM_004239.4 splice_donor
NM_004239.4 splice_donor
Scores
5
1
1
Splicing: ADA: 0.9926
1
1
Clinical Significance
Conservation
PhyloP100: 6.77
Genes affected
TRIP11 (HGNC:12305): (thyroid hormone receptor interactor 11) This gene was identified based on the interaction of its protein product with thyroid hormone receptor beta. This protein is associated with the Golgi apparatus. The N-terminal region of the protein binds Golgi membranes and the C-terminal region binds the minus ends of microtubules; thus, the protein is thought to play a role in assembly and maintenance of the Golgi ribbon structure around the centrosome. Mutations in this gene cause achondrogenesis type IA.[provided by RefSeq, Mar 2010]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 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, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| TRIP11 | NM_004239.4 | c.5719+2T>C | splice_donor_variant | ENST00000267622.8 | |||
| TRIP11 | NM_001321851.1 | c.5716+2T>C | splice_donor_variant | ||||
| TRIP11 | XM_047431935.1 | c.4393+2T>C | splice_donor_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TRIP11 | ENST00000267622.8 | c.5719+2T>C | splice_donor_variant | 1 | NM_004239.4 | P1 | |||
| TRIP11 | ENST00000554357.5 | c.4865+2T>C | splice_donor_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.000131 AC: 20AN: 152190Hom.: 0 Cov.: 33
GnomAD3 genomes
?
AF:
AC:
20
AN:
152190
Hom.:
Cov.:
33
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: 0.0000812 AC: 20AN: 246318Hom.: 0 AF XY: 0.0000525 AC XY: 7AN XY: 133444
GnomAD3 exomes
AF:
AC:
20
AN:
246318
Hom.:
AF XY:
AC XY:
7
AN XY:
133444
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: 0.000245 AC: 357AN: 1455286Hom.: 0 Cov.: 30 AF XY: 0.000220 AC XY: 159AN XY: 723668
GnomAD4 exome
AF:
AC:
357
AN:
1455286
Hom.:
Cov.:
30
AF XY:
AC XY:
159
AN XY:
723668
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: 0.000131 AC: 20AN: 152190Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74362
GnomAD4 genome
?
AF:
AC:
20
AN:
152190
Hom.:
Cov.:
33
AF XY:
AC XY:
6
AN XY:
74362
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:
TwinsUK
AF:
AC:
0
ALSPAC
AF:
AC:
1
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
2
ExAC
?
AF:
AC:
7
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 19, 2018 | Variant classified as Uncertain Significance - Favor Pathogenic. The c.5719+2T>C variant in TRIP11 has not been reported in individuals with Achondrogenesis typ e 1A but has been identified in 0.016% (20/127174) of European chromosomes by gn omAD (http://gnomad.broadinstitute.org). This variant occurs within the canonica l splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein; however, this splice variant disrupts the donor spl ice site of the penultimate exon and therefore may escape nonsense mediated deca y. Additionally, no loss of function variants downstream of this variant have be en reported in individuals with disease. In summary, while there is some suspici on for a pathogenic role, the clinical significance of the c.5719+2T>C variant i s uncertain. ACMG/AMP Criteria applied: PVS1_Moderate. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 16, 2023 | Variant summary: TRIP11 c.5719+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. To our knowledge c.5719+2T>C has not been reported in the literature in individuals affected with TRIP11-Related Disorders and no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30609409, 33578785). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 14, 2022 | Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Has not been previously reported as pathogenic or benign in association with a TRIPP11-related disorder to our knowledge; This variant is associated with the following publications: (PMID: 30609409) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 02, 2023 | - - |
Achondrogenesis, type IA Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 19, 2022 | This sequence change affects a donor splice site in intron 20 of the TRIP11 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs199736345, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TRIP11-related conditions. ClinVar contains an entry for this variant (Variation ID: 505515). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Dec 25, 2018 | This variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change. No publications were found based on this search. Due to the potential impact of splice donor variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at