15-43403697-G-T
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_014444.5(TUBGCP4):c.1746G>T(p.Leu582Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000687 in 1,612,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00072 ( 0 hom. )
Consequence
TUBGCP4
NM_014444.5 synonymous
NM_014444.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 2.03
Genes affected
TUBGCP4 (HGNC:16691): (tubulin gamma complex component 4) This gene encodes a component of the gamma-tubulin ring complex, which is required for microtubule nucleation. In mammalian cells, the protein localizes to centrosomes in association with gamma-tubulin. Crystal structure analysis revealed a structure composed of five helical bundles arranged around conserved hydrophobic cores. An exposed surface area located in the C-terminal domain is essential and sufficient for direct binding to gamma-tubulin. Mutations in this gene that alter microtubule organization are associated with microcephaly and chorioretinopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2015]
TP53BP1 (HGNC:11999): (tumor protein p53 binding protein 1) This gene encodes a protein that functions in the DNA double-strand break repair pathway choice, promoting non-homologous end joining (NHEJ) pathways, and limiting homologous recombination. This protein plays multiple roles in the DNA damage response, including promoting checkpoint signaling following DNA damage, acting as a scaffold for recruitment of DNA damage response proteins to damaged chromatin, and promoting NHEJ pathways by limiting end resection following a double-strand break. These roles are also important during V(D)J recombination, class switch recombination and at unprotected telomeres. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-43403697-G-T is Pathogenic according to our data. Variant chr15-43403697-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-43403697-G-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TUBGCP4 | ENST00000564079.6 | c.1746G>T | p.Leu582Leu | synonymous_variant | Exon 16 of 18 | 1 | NM_014444.5 | ENSP00000456648.2 | ||
| TP53BP1 | ENST00000382044 | c.*3686C>A | 3_prime_UTR_variant | Exon 28 of 28 | 1 | NM_001141980.3 | ENSP00000371475.5 |
Frequencies
GnomAD3 genomes 0.000342 AC: 52AN: 152142Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000297 AC: 74AN: 248998Hom.: 0 AF XY: 0.000370 AC XY: 50AN XY: 135084
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GnomAD4 exome AF: 0.000723 AC: 1056AN: 1460206Hom.: 0 Cov.: 30 AF XY: 0.000736 AC XY: 535AN XY: 726430
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GnomAD4 genome 0.000342 AC: 52AN: 152260Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23AN XY: 74444
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Microcephaly and chorioretinopathy 3 Pathogenic:6
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with microcephaly and chorioretinopathy, 3, (MIM#616335). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. RT-PCR of cDNA derived from an affected individual's fibroblasts has demonstrated this variant causes inframe exon 16 skipping, but also the retention of wildtype protein. The proportion of wildtype and mutant protein is unclear (PMID: 25817018). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (86 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is located in the annotated Gamma tubulin complex component C-terminal domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as likely pathogenic or pathogenic, and is a recurring variant observed in compound heterozygous individuals with microcephaly, chorioretinopathy and intellectual disability (ClinVar, PMID: 25817018), and a homozygous individual with autism and ectasia of the optic nerve sheaths with no microcephaly or chorioretinopathy (PMID: 35418825). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 02, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 04, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
| Pathogenic, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 26, 2018 | DNA sequence analysis of the TUBGCP4 gene demonstrated a synonymous pathogenic sequence change, c.1746G>T p. Leu582Leu, in exon 16, that does not result in an amino acid substitution. This silent sequence change was previously reported in in the compound heterozygous state in a patient with TUBGCP4-related microcephaly and chorioretinopathy (PMID: 25817018). Functional analysis of individual fibroblasts demonstrated that the c.1746G>T variant resulted in skipping of exon 16, which led to a reduction of the protein product (PMID: 25817018). - |
| Likely pathogenic, criteria provided, single submitter | research | Laboratory of Human Genetics, Universidade de São Paulo | Jun 27, 2022 | This variant meets our criteria to be classified as pathogenic based upon segregation studies, low frequency in control samples, and in-silico evaluation of pathogenicity. - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | May 23, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 23, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 06, 2025 | This sequence change affects codon 583 of the TUBGCP4 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TUBGCP4 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs200092283, gnomAD 0.05%). This variant has been observed in individual(s) with microcephaly and chorioretinal dysplasia (PMID: 25817018). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 190123). Studies have shown that this variant results in skipping of exon 16, but is expected to preserve the integrity of the reading-frame (PMID: 25817018). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 30, 2024 | Reported in the homozygous state in a proband with an atypical phenotype of autism spectrum disorder and ectasia of the optic nerve sheaths with a normal head circumference and no retinal anomalies (PMID: 35418825); Functional studies using fibroblasts from a patient suggest that the c.1746 G>T variant resulted in skipping of exon 16, which led to a reduction of the protein product, abnormal microtubule organization, and altered cell morphology (PMID: 25817018); This variant is associated with the following publications: (PMID: 25817018, 31847883, 32270730, 33137195, 31964843, 35418825) - |
Autosomal recessive chorioretinopathy-microcephaly syndrome Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 04, 2018 | The p.Leu582Leu variant in TUBGCP4 has been reported in the compound heterozygou s state (with loss of function variants) in 3 individuals with microcephaly with chorioretinopathy and segregated with disease in 1 affected relative (Scheideck er 2015). It has also been identified in 0.05% (66/128464) of European chromosom es by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID 190123). In vitro functional studies support a splicing impact af fecting protein function (Scheidecker 2015). In summary, although additional stu dies are required to fully establish its clinical significance, this variant mee ts criteria to be classified as likely pathogenic for autosomal recessive microc ephaly with chorioretinopathy. ACMG/AMP Criteria applied: PM3_Strong, PP1, PS3_S upporting. - |
TUBGCP4-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 03, 2025 | This variant has been reported in the compound heterozygous state in individuals with autosomal recessive microcephaly and chorioretinopathy and segregated with disease in families (see, for example, Scheidecker et al. 2015. PubMed ID: 25817018; Da Palma et al. 2020. PubMed ID: 32270730; Yahalom et al. 2023. PubMed ID: 37038737). It has also been reported in an individual with autism who did not present with microcephaly and chorioretinopathy (Martín Fernández-Mayoralas et al. 2021. PubMed ID: 35418825). RT-PCR studies indicated skipping of exon 16 (Scheidecker et al. 2015. PubMed ID: 25817018). This variant is reported in 0.051% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Details are displayed if max score is > 0.2
DS_AL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at