1-235380107-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003193.5(TBCE):c.58C>T(p.His20Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TBCE NM_003193.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.784

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.102071375).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBCE	NM_003193.5	c.58C>T	p.His20Tyr	missense_variant	2/17	ENST00000642610.2
TBCE	NM_001287801.2	c.58C>T	p.His20Tyr	missense_variant	2/18
TBCE	NM_001079515.3	c.58C>T	p.His20Tyr	missense_variant	2/17
TBCE	NM_001287802.2	c.-253C>T		5_prime_UTR_variant	2/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBCE	ENST00000642610.2	c.58C>T	p.His20Tyr	missense_variant	2/17		NM_003193.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461162 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726900

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 20, 2022

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 20 of the TBCE protein (p.His20Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TBCE-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The tyrosine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	0.062
Dann	Benign	0.24
DEOGEN2	Benign	0.39	T;T;T;T;T;.;.;T;T;T;.;.;.;.;.;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.013	N
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.10	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	-1.6	N;N;N;N;N;.;.;N;N;N;.;.;.;.;N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.48	T
Polyphen		0.0	B;B;B;B;B;.;.;B;B;B;.;.;.;.;.;.;.
Vest4		0.17, 0.18
MutPred		0.72		Gain of phosphorylation at H20 (P = 0.0137);Gain of phosphorylation at H20 (P = 0.0137);Gain of phosphorylation at H20 (P = 0.0137);Gain of phosphorylation at H20 (P = 0.0137);Gain of phosphorylation at H20 (P = 0.0137);Gain of phosphorylation at H20 (P = 0.0137);Gain of phosphorylation at H20 (P = 0.0137);Gain of phosphorylation at H20 (P = 0.0137);Gain of phosphorylation at H20 (P = 0.0137);Gain of phosphorylation at H20 (P = 0.0137);Gain of phosphorylation at H20 (P = 0.0137);Gain of phosphorylation at H20 (P = 0.0137);Gain of phosphorylation at H20 (P = 0.0137);Gain of phosphorylation at H20 (P = 0.0137);Gain of phosphorylation at H20 (P = 0.0137);Gain of phosphorylation at H20 (P = 0.0137);Gain of phosphorylation at H20 (P = 0.0137);
MVP		0.54
MPC		0.25
ClinPred		0.037	T
GERP RS		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.030
gMVP		0.46

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-235543422;