rs750781063

chr1-235436567-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003193.5(TBCE):c.924del(p.Leu309Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TBCE NM_003193.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.89

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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
• PP5: Variant 1-235436567-TC-T is Pathogenic according to our data. Variant chr1-235436567-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 372200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-235436567-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBCE	NM_003193.5	c.924del	p.Leu309Ter	frameshift_variant	11/17	ENST00000642610.2
TBCE	NM_001287801.2	c.1077del	p.Leu360Ter	frameshift_variant	12/18
TBCE	NM_001079515.3	c.924del	p.Leu309Ter	frameshift_variant	11/17
TBCE	NM_001287802.2	c.585del	p.Leu196Ter	frameshift_variant	10/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBCE	ENST00000642610.2	c.924del	p.Leu309Ter	frameshift_variant	11/17		NM_003193.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251488 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461830 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Encephalopathy, progressive, with amyotrophy and optic atrophy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 29, 2016

- -

TBCE-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 22, 2022

Variant summary: TBCE c.924delC (p.Leu309X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position is reported in HGMD and classified as pathogenic. The variant allele was found at a frequency of 1.6e-05 in 251488 control chromosomes. c.924delC has been reported in the literature in individuals affected with TBCE-Related Disorder (Sferra_2016, Battini_2021). These data indicate that the variant is associated with disease. One publication reports experimental evidence evaluating an impact on mRNA and protein expression, which found the frameshift variant to be undetectable at the mRNA level, indicating nonsense-mediated RNA decay (Sferra_2016). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 22, 2023

ClinVar contains an entry for this variant (Variation ID: 372200). For these reasons, this variant has been classified as Pathogenic. This variant is also known as c.1076delC. This premature translational stop signal has been observed in individual(s) with progressive encephalopathy with amyotrophy and optic atrophy (PMID: 27666369, 34134906). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs750781063, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Leu309*) in the TBCE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TBCE are known to be pathogenic (PMID: 27666369, 34134906, 34356170). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs750781063; hg19: chr1-235599882;