1-235380138-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003193.5(TBCE):c.89C>T(p.Pro30Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,428 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 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: 3.68

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBCE	NM_003193.5	c.89C>T	p.Pro30Leu	missense_variant	2/17	ENST00000642610.2
TBCE	NM_001287801.2	c.89C>T	p.Pro30Leu	missense_variant	2/18
TBCE	NM_001079515.3	c.89C>T	p.Pro30Leu	missense_variant	2/17
TBCE	NM_001287802.2	c.-222C>T		5_prime_UTR_variant	2/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBCE	ENST00000642610.2	c.89C>T	p.Pro30Leu	missense_variant	2/17		NM_003193.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459428 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726028

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: 9.01e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pituitary stalk interruption syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Human Developmental Genetics, Institut Pasteur

Sep 10, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;D;D;D;D;.;.;D;D;D;.;.;.;.;.;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.028	D
MutationAssessor	Uncertain	2.1	M;M;M;M;M;.;.;M;M;M;.;.;.;.;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
Polyphen		0.42	B;B;B;B;B;.;.;B;B;B;.;.;.;.;.;.;.
Vest4		0.57, 0.57, 0.57
MutPred		0.74		Loss of catalytic residue at P30 (P = 0.0222);Loss of catalytic residue at P30 (P = 0.0222);Loss of catalytic residue at P30 (P = 0.0222);Loss of catalytic residue at P30 (P = 0.0222);Loss of catalytic residue at P30 (P = 0.0222);Loss of catalytic residue at P30 (P = 0.0222);Loss of catalytic residue at P30 (P = 0.0222);Loss of catalytic residue at P30 (P = 0.0222);Loss of catalytic residue at P30 (P = 0.0222);Loss of catalytic residue at P30 (P = 0.0222);Loss of catalytic residue at P30 (P = 0.0222);Loss of catalytic residue at P30 (P = 0.0222);Loss of catalytic residue at P30 (P = 0.0222);Loss of catalytic residue at P30 (P = 0.0222);Loss of catalytic residue at P30 (P = 0.0222);Loss of catalytic residue at P30 (P = 0.0222);Loss of catalytic residue at P30 (P = 0.0222);
MVP		0.84
MPC		0.81
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.27
gMVP		0.69

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: chr1-235543453;