chr1-235427143-T-A

Variant names:

• chr1-235427143-T-A
• rs780472451
• NM_003193.5:c.464T>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_003193.5(TBCE):​c.464T>A​(p.Ile155Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000412 in 1,455,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TBCE NM_003193.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.79
• Publications: 5 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), G2P, Orphanet
• 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, LIMITED Submitted by: Ambry Genetics, G2P
• autosomal recessive Kenny-Caffey syndrome

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

ENSG00000285053 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914
• PP5: Variant 1-235427143-T-A is Pathogenic according to our data. Variant chr1-235427143-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 372201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBCE	NM_003193.5	c.464T>A	p.Ile155Asn	missense_variant	Exon 6 of 17	ENST00000642610.2	NP_003184.1
TBCE	NM_001287801.2	c.464T>A	p.Ile155Asn	missense_variant	Exon 6 of 18		NP_001274730.1
TBCE	NM_001079515.3	c.464T>A	p.Ile155Asn	missense_variant	Exon 6 of 17		NP_001072983.1
TBCE	NM_001287802.2	c.125T>A	p.Ile42Asn	missense_variant	Exon 5 of 16		NP_001274731.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBCE	ENST00000642610.2	c.464T>A	p.Ile155Asn	missense_variant	Exon 6 of 17		NM_003193.5	ENSP00000494796.1
ENSG00000285053	ENST00000647186.1	c.464T>A	p.Ile155Asn	missense_variant	Exon 8 of 19			ENSP00000494775.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251330 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1455882 Hom.: 0 Cov.: 29 AF XY: 0.00000414 AC XY: 3 AN XY: 724692

African (AFR) AF: 0.00 AC: 0 AN: 33338

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000542 AC: 6 AN: 1106658

Other (OTH) AF: 0.00 AC: 0 AN: 60182

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 155 of the TBCE protein (p.Ile155Asn). This variant is present in population databases (rs780472451, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of progressive encephalopathy with amyotrophy and optic atrophy (PMID: 27666369). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 372201). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TBCE protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Feb 17, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in GeneDX; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27666369) -

May 12, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TBCE-related disorder Pathogenic:1

Apr 08, 2025

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TBCE c.464T>A (p.Ile155Asn) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.464T>A has been reported in the literature in multiple individuals affected with TBCE-Related Disorder (example, Sferra_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in almost diminished normal expression and microtubule polymerization in patients fibroblasts (Sferra_2016). The following publication has been ascertained in the context of this evaluation (PMID: 27666369). ClinVar contains an entry for this variant (Variation ID: 372201). Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Nov 29, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	.;D;D;D;D;D;.;D;D;D;.;.;.;.;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	.;.;.;.;.;.;.;.;.;.;D;D;T;D;D;D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Pathogenic	3.5	.;H;H;H;H;H;.;H;H;H;.;.;.;.;H;.
PhyloP100		4.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.9	.;.;.;.;.;.;.;.;.;D;.;.;.;.;D;.
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	.;.;.;.;.;.;.;.;.;D;.;.;.;.;D;.
Sift4G	Pathogenic	0.0010	.;.;.;.;.;.;.;.;.;D;.;.;.;.;D;.
Polyphen		1.0	.;D;D;D;D;D;.;D;D;D;.;.;.;.;.;.
Vest4		0.88, 0.84
MutPred		0.82		.;Gain of disorder (P = 0.0124);Gain of disorder (P = 0.0124);Gain of disorder (P = 0.0124);Gain of disorder (P = 0.0124);Gain of disorder (P = 0.0124);Gain of disorder (P = 0.0124);Gain of disorder (P = 0.0124);Gain of disorder (P = 0.0124);Gain of disorder (P = 0.0124);Gain of disorder (P = 0.0124);.;.;.;Gain of disorder (P = 0.0124);Gain of disorder (P = 0.0124);
MVP		0.75
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.44
gMVP		0.80
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs780472451; hg19: chr1-235590458;