rs780472451

Positions:

• chr1-235427143-T-A

Variant summary

Our verdict is Pathogenic. Variant got 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:4
• Conservation: PhyloP100: 4.79

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.

• 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 [Likely_pathogenic]. Clinvar id is 372201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-235427143-T-A is described in UniProt as null. Variant chr1-235427143-T-A is described in UniProt as null. Variant chr1-235427143-T-A is described in UniProt as null. Variant chr1-235427143-T-A is described in UniProt as null. Variant chr1-235427143-T-A is described in UniProt as null. Variant chr1-235427143-T-A is described in UniProt as null. Variant chr1-235427143-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBCE	NM_003193.5	c.464T>A	p.Ile155Asn	missense_variant	6/17	ENST00000642610.2
TBCE	NM_001287801.2	c.464T>A	p.Ile155Asn	missense_variant	6/18
TBCE	NM_001079515.3	c.464T>A	p.Ile155Asn	missense_variant	6/17
TBCE	NM_001287802.2	c.125T>A	p.Ile42Asn	missense_variant	5/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBCE	ENST00000642610.2	c.464T>A	p.Ile155Asn	missense_variant	6/17		NM_003193.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000542

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 12, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 17, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2021	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) -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 29, 2016

- -

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
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.91	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
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.50	T
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

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: rs780472451; hg19: chr1-235590458;