NM_003193.5:c.66_67delAG

Variant names:

• chr1-235380114-CAG-C
• rs1572324681
• NM_003193.5:c.66_67delAG

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_67delAG​(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]

ENSG00000285053 (HGNC:):

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 29 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 rank	MANE	Protein	UniProt
TBCE	NM_003193.5	c.66_67delAG	p.Val23ThrfsTer27	frameshift_variant	Exon 2 of 17	ENST00000642610.2	NP_003184.1
TBCE	NM_001287801.2	c.66_67delAG	p.Val23ThrfsTer27	frameshift_variant	Exon 2 of 18		NP_001274730.1
TBCE	NM_001079515.3	c.66_67delAG	p.Val23ThrfsTer27	frameshift_variant	Exon 2 of 17		NP_001072983.1
TBCE	NM_001287802.2	c.-245_-244delAG		5_prime_UTR_variant	Exon 2 of 16		NP_001274731.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBCE	ENST00000642610.2	c.66_67delAG	p.Val23ThrfsTer27	frameshift_variant	Exon 2 of 17		NM_003193.5	ENSP00000494796.1
ENSG00000285053	ENST00000645655.1	c.66_67delAG	p.Val23ThrfsTer27	frameshift_variant	Exon 5 of 20			ENSP00000495202.1

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

Sep 05, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jun 28, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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). -

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;