1-235380084-G-A

Position:

• chr1-235380084-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.730

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=0.12896237).

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251482 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135914

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: 18 AN: 1461598 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 727116

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.: 31

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

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	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	18
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	D
LIST_S2	Benign	0.67	.;.;.;.;.;.;.;.;.;.;T;T;T;T;T;T;T
M_CAP	Benign	0.029	D
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	T
MutationAssessor	Benign	0.83	L;L;L;L;L;.;.;L;L;L;.;.;.;.;L;.;.
MutationTaster	Benign	0.79	D;D;D
PrimateAI	Benign	0.34	T
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	T
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

Other links and lift over

dbSNP: rs201164091; hg19: chr1-235543399;