rs1572324681

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PS3 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 (★). ClinVar reports functional evidence for this variant: "SCV001591930: 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).".

• 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
• Publications: 0 publications found

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]

TBCE Gene-Disease associations (from GenCC):

• hypoparathyroidism-retardation-dysmorphism syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, G2P
• early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• encephalopathy, progressive, with amyotrophy and optic atrophy

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, ClinGen, G2P, Ambry Genetics
• autosomal recessive Kenny-Caffey syndrome

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet

ENSG00000285053 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 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 49 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001591930: 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).
• 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 VariationId is 5291.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003193.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBCE	NM_003193.5	MANE Select	c.66_67delAG	p.Val23ThrfsTer27	frameshift	Exon 2 of 17	NP_003184.1	Q15813-1
	TBCE	NM_001287801.2		c.66_67delAG	p.Val23ThrfsTer27	frameshift	Exon 2 of 18	NP_001274730.1	Q15813-2
	TBCE	NM_001079515.3		c.66_67delAG	p.Val23ThrfsTer27	frameshift	Exon 2 of 17	NP_001072983.1	Q15813-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBCE	ENST00000642610.2	MANE Select	c.66_67delAG	p.Val23ThrfsTer27	frameshift	Exon 2 of 17	ENSP00000494796.1	Q15813-1
	ENSG00000285053	ENST00000647186.1		c.66_67delAG	p.Val23ThrfsTer27	frameshift	Exon 4 of 19	ENSP00000494775.1
	TBCE	ENST00000366601.8	TSL:1	c.66_67delAG	p.Val23ThrfsTer27	frameshift	Exon 2 of 15	ENSP00000355560.4	A0A2U3TZJ6

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hypoparathyroidism-retardation-dysmorphism syndrome (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.7
Mutation Taster		=9/191	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1572324681; hg19: chr1-235543429;