chr1-235380084-G-A

Position:

chr1-235380084-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003193.5(TBCE):c.35G>A(p.Arg12Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 0.000012 ( 0 hom. )

Consequence

TBCE
NM_003193.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.730

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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=0.12896237).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TBCE	NM_003193.5 linkuse as main transcript	c.35G>A	p.Arg12Gln	missense_variant	2/17	ENST00000642610.2
TBCE	NM_001287801.2 linkuse as main transcript	c.35G>A	p.Arg12Gln	missense_variant	2/18
TBCE	NM_001079515.3 linkuse as main transcript	c.35G>A	p.Arg12Gln	missense_variant	2/17
TBCE	NM_001287802.2 linkuse as main transcript	c.-276G>A		5_prime_UTR_variant	2/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBCE	ENST00000642610.2 linkuse as main transcript	c.35G>A	p.Arg12Gln	missense_variant	2/17		NM_003193.5	P1	Q15813-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251482

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135914

show subpopulations

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 SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461598

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727116

show subpopulations

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:

0.000151

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 12, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 12 of the TBCE protein (p.Arg12Gln). This variant is present in population databases (rs201164091, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TBCE-related conditions. ClinVar contains an entry for this variant (Variation ID: 1411006). 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 glutamine 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

0.096

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.42

T;T;T;T;T;.;.;T;T;T;.;.;.;.;.;.;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.67

.;.;.;.;.;.;.;.;.;.;T;T;T;T;T;T;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.13

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.83

L;L;L;L;L;.;.;L;L;L;.;.;.;.;L;.;.

MutationTaster

Benign

0.79

D;D;D

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.96

.;.;.;.;.;.;.;.;.;N;.;.;.;.;N;N;.

REVEL

Benign

0.082

Sift

Benign

0.13

.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;T;.

Sift4G

Benign

0.067

.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;T;.

Polyphen

0.13

B;B;B;B;B;.;.;B;B;B;.;.;.;.;.;.;.

Vest4

0.29, 0.33, 0.29

MutPred

0.63

Loss of MoRF binding (P = 0.118);Loss of MoRF binding (P = 0.118);Loss of MoRF binding (P = 0.118);Loss of MoRF binding (P = 0.118);Loss of MoRF binding (P = 0.118);Loss of MoRF binding (P = 0.118);Loss of MoRF binding (P = 0.118);Loss of MoRF binding (P = 0.118);Loss of MoRF binding (P = 0.118);Loss of MoRF binding (P = 0.118);Loss of MoRF binding (P = 0.118);Loss of MoRF binding (P = 0.118);Loss of MoRF binding (P = 0.118);Loss of MoRF binding (P = 0.118);Loss of MoRF binding (P = 0.118);Loss of MoRF binding (P = 0.118);Loss of MoRF binding (P = 0.118);

MVP

0.63

MPC

0.36

ClinPred

0.12

GERP RS

1.6

Varity_R

0.052

gMVP

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over