chr1-235380150-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_003193.5(TBCE):c.100+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000685 in 1,590,918 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
Consequence
NM_003193.5 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TBCE | NM_003193.5 | c.100+1G>A | splice_donor_variant, intron_variant | Intron 2 of 16 | ENST00000642610.2 | NP_003184.1 | ||
TBCE | NM_001287801.2 | c.100+1G>A | splice_donor_variant, intron_variant | Intron 2 of 17 | NP_001274730.1 | |||
TBCE | NM_001079515.3 | c.100+1G>A | splice_donor_variant, intron_variant | Intron 2 of 16 | NP_001072983.1 | |||
TBCE | NM_001287802.2 | c.-211+1G>A | splice_donor_variant, intron_variant | Intron 2 of 15 | NP_001274731.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TBCE | ENST00000642610.2 | c.100+1G>A | splice_donor_variant, intron_variant | Intron 2 of 16 | NM_003193.5 | ENSP00000494796.1 | ||||
ENSG00000285053 | ENST00000645655.1 | c.100+1G>A | splice_donor_variant, intron_variant | Intron 5 of 19 | ENSP00000495202.1 |
Frequencies
GnomAD3 genomes AF: 0.0000871 AC: 13AN: 149328Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000800 AC: 20AN: 249900Hom.: 0 AF XY: 0.0000666 AC XY: 9AN XY: 135156
GnomAD4 exome AF: 0.0000666 AC: 96AN: 1441590Hom.: 0 Cov.: 31 AF XY: 0.0000682 AC XY: 49AN XY: 717982
GnomAD4 genome AF: 0.0000871 AC: 13AN: 149328Hom.: 0 Cov.: 31 AF XY: 0.0000964 AC XY: 7AN XY: 72632
ClinVar
Submissions by phenotype
not provided Pathogenic:3
TBCE: PVS1, PM2 -
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; This variant is associated with the following publications: (PMID: 35432193) -
This sequence change affects a donor splice site in intron 2 of the TBCE 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 TBCE are known to be pathogenic (PMID: 27666369, 34134906, 34356170). This variant is present in population databases (rs200356271, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with TBCE-related conditions (PMID: 35432193). ClinVar contains an entry for this variant (Variation ID: 631595). 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 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. -
Autosomal recessive Kenny-Caffey syndrome Pathogenic:2Other:1
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Criteria applied: PVS1,PM3,PM2_SUP -
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2. -
TBCE-related disorder Pathogenic:2
Variant summary: TBCE c.100+1G>A 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: four predict the variant abolishes a 5' splicing donor site, while three predict the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-05 in 249900 control chromosomes (gnomAD). This frequency allows no conclusions about variant significance. The variant, c.100+1G>A, has been reported in the literature in a homozygous individual affected with TBCE-Related Disorder (Globa_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and reported the variant with conflicting assessments (VUS (n=2), likely pathogenic (n=2)). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
The TBCE c.100+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was previously described in the homozygous state in an individual with inguinal bilateral cryptorchidism, cognitive impairment, dysmorphic features, recurrent infections, and dwarfism (Globa et al. 2022. PubMed ID: 35432193). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in TBCE are expected to be pathogenic. This variant is interpreted as likely pathogenic. -
Disorder of sexual differentiation Pathogenic:1
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Autosomal recessive Kenny-Caffey syndrome;C1855840:Hypoparathyroidism-retardation-dysmorphism syndrome;C4310667:Encephalopathy, progressive, with amyotrophy and optic atrophy Pathogenic:1
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Hypoparathyroidism-retardation-dysmorphism syndrome Uncertain:1
The TBCE c.100+1G>A 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 hypoparathyroidism-retardation-dysmorphism syndrome. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at