11-121058389-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001363644.2(TBCEL):c.757A>C(p.Lys253Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBCEL NM_001363644.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.27

Genes affected

TBCEL (HGNC:28115): (tubulin folding cofactor E like) Predicted to enable alpha-tubulin binding activity. Predicted to be involved in microtubule cytoskeleton organization; post-chaperonin tubulin folding pathway; and tubulin complex assembly. Predicted to be located in cytoskeleton. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TBCEL-TECTA (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TBCEL
• BP4: Computational evidence support a benign effect (MetaRNN=0.2625512).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBCEL	NM_001363644.2	c.757A>C	p.Lys253Gln	missense_variant	7/9	ENST00000683345.1
TBCEL-TECTA	NM_001378761.1	c.757A>C	p.Lys253Gln	missense_variant	6/30
TBCEL	NM_001130047.3	c.757A>C	p.Lys253Gln	missense_variant	6/8
TBCEL	NM_152715.5	c.757A>C	p.Lys253Gln	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBCEL	ENST00000683345.1	c.757A>C	p.Lys253Gln	missense_variant	7/9		NM_001363644.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 2024

The c.757A>C (p.K253Q) alteration is located in exon 6 (coding exon 5) of the TBCEL gene. This alteration results from a A to C substitution at nucleotide position 757, causing the lysine (K) at amino acid position 253 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.024	T;T;.;.
Eigen	Benign	0.065
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.26	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	L;L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.66	N;N;N;.
REVEL	Benign	0.12
Sift	Benign	0.51	T;T;T;.
Sift4G	Uncertain	0.025	D;D;T;.
Polyphen		0.013	B;B;.;.
Vest4		0.39
MutPred		0.35		Loss of ubiquitination at K253 (P = 0.0148);Loss of ubiquitination at K253 (P = 0.0148);.;.;
MVP		0.30
MPC		1.3
ClinPred		0.66	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.63

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: chr11-120929098;