11-121045812-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001363644.2(TBCEL):c.122C>G(p.Ser41Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,438,132 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S41F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TBCEL NM_001363644.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.79

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TBCEL

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBCEL	NM_001363644.2	c.122C>G	p.Ser41Cys	missense_variant	3/9	ENST00000683345.1
TBCEL-TECTA	NM_001378761.1	c.122C>G	p.Ser41Cys	missense_variant	2/30
TBCEL	NM_001130047.3	c.122C>G	p.Ser41Cys	missense_variant	2/8
TBCEL	NM_152715.5	c.122C>G	p.Ser41Cys	missense_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBCEL	ENST00000683345.1	c.122C>G	p.Ser41Cys	missense_variant	3/9		NM_001363644.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1438132 Hom.: 0 Cov.: 30 AF XY: 0.00000280 AC XY: 2 AN XY: 715010

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000262

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: 0.00

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

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

Jun 02, 2023

The c.122C>G (p.S41C) alteration is located in exon 2 (coding exon 1) of the TBCEL gene. This alteration results from a C to G substitution at nucleotide position 122, causing the serine (S) at amino acid position 41 to be replaced by a cysteine (C). 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	Uncertain	0.37
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Benign	0.070	T;T;T;T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.60	D;D;D;D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.9	M;.;M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.3	N;D;N;D;.
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;.
Polyphen		1.0	D;.;D;.;.
Vest4		0.66
MutPred		0.53		Loss of disorder (P = 0.0085);Loss of disorder (P = 0.0085);Loss of disorder (P = 0.0085);Loss of disorder (P = 0.0085);.;
MVP		0.47
MPC		1.8
ClinPred		0.93	D
GERP RS		5.6
Varity_R		0.36
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

LitVar

Other links and lift over

dbSNP: rs1028764515; hg19: chr11-120916521;