1-235380114-CAG-C

Position:

• chr1-235380114-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003193.5(TBCE):​c.66_67del​(p.Val23ThrfsTer27) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TBCE NM_003193.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.66

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 25 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-235380114-CAG-C is Pathogenic according to our data. Variant chr1-235380114-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 5291.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBCE	NM_003193.5	c.66_67del	p.Val23ThrfsTer27	frameshift_variant	2/17	ENST00000642610.2
TBCE	NM_001079515.3	c.66_67del	p.Val23ThrfsTer27	frameshift_variant	2/17
TBCE	NM_001287801.2	c.66_67del	p.Val23ThrfsTer27	frameshift_variant	2/18
TBCE	NM_001287802.2	c.-245_-244del		5_prime_UTR_variant	2/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBCE	ENST00000642610.2	c.66_67del	p.Val23ThrfsTer27	frameshift_variant	2/17		NM_003193.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hypoparathyroidism-retardation-dysmorphism syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 05, 2006

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 28, 2018

This sequence change creates a premature translational stop signal (p.Val23Thrfs*27) in the TBCE gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with congenital hypoparathyroidism, intellectual disability, facial dysmorphism, and extreme growth failure (known as HRD or Sanjad–Sakati syndrome) (PMID: 12389028). Experimental studies have shown that this variant does not result in nonsense-mediated decay of the mRNA, but instead results in the production of an N-terminally disrupted protein that retains TBCE activity in vitro. However in cells derived from an affected individual this altered protein was found to be intrinsically unstable and to ultimately result in loss of activity (PMID: 16938882). Loss-of-function variants in TBCE are known to be pathogenic (PMID: 12389028, 12389029). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1572324681; hg19: chr1-235543429;