chr1-235448358-C-CAATTCAAAAGGTGAAGGGATTGCTG
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_003193.5(TBCE):c.1410_1434dup(p.Ser479AsnfsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 151,994 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000023 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
TBCE
NM_003193.5 frameshift
NM_003193.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.0670
Genes affected
TBCE (HGNC:11582): (tubulin folding cofactor E) Cofactor E is one of four proteins (cofactors A, D, E, and C) involved in the pathway leading to correctly folded beta-tubulin from folding intermediates. Cofactors A and D are believed to play a role in capturing and stabilizing beta-tubulin intermediates in a quasi-native confirmation. Cofactor E binds to the cofactor D/beta-tubulin complex; interaction with cofactor C then causes the release of beta-tubulin polypeptides that are committed to the native state. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]
B3GALNT2 (HGNC:28596): (beta-1,3-N-acetylgalactosaminyltransferase 2) This gene encodes a member of the glycosyltransferase 31 family. The encoded protein synthesizes GalNAc:beta-1,3GlcNAc, a novel carbohydrate structure, on N- and O-glycans. Alternatively spliced transcript variants that encode different isoforms have been described. [provided by RefSeq, Mar 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TBCE | NM_003193.5 | c.1410_1434dup | p.Ser479AsnfsTer24 | frameshift_variant | 16/17 | ENST00000642610.2 | |
B3GALNT2 | NM_152490.5 | c.*1847_*1848insCAGCAATCCCTTCACCTTTTGAATT | 3_prime_UTR_variant | 12/12 | ENST00000366600.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TBCE | ENST00000642610.2 | c.1410_1434dup | p.Ser479AsnfsTer24 | frameshift_variant | 16/17 | NM_003193.5 | P1 | ||
B3GALNT2 | ENST00000366600.8 | c.*1847_*1848insCAGCAATCCCTTCACCTTTTGAATT | 3_prime_UTR_variant | 12/12 | 1 | NM_152490.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 151994Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250054Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135292
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000233 AC: 34AN: 1461784Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11AN XY: 727200
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Encephalopathy, progressive, with amyotrophy and optic atrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 26, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VUS – 3B. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0205 - Variant is predicted to result in a truncated protein with less than 1/3 of the protein affected (exon 16 of 17). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (4 heterozygotes, 0 homozygotes). (P) 0600 - Variant is predicted to truncate part of the ubiquitin-like domain (PDB, NCBI). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at