11-121055285-G-A

Variant names:

• chr11-121055285-G-A
• rs1457306216
• NM_001363644.2:c.689G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001363644.2(TBCEL):​c.689G>A​(p.Arg230Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,457,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TBCEL NM_001363644.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.81
• Publications: 0 publications found

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:54857): (TBCEL-TECTA readthrough) 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 active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37064528).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBCEL	NM_001363644.2	c.689G>A	p.Arg230Gln	missense_variant	Exon 6 of 9	ENST00000683345.1	NP_001350573.1
TBCEL-TECTA	NM_001378761.1	c.689G>A	p.Arg230Gln	missense_variant	Exon 5 of 30		NP_001365690.1
TBCEL	NM_001130047.3	c.689G>A	p.Arg230Gln	missense_variant	Exon 5 of 8		NP_001123519.1
TBCEL	NM_152715.5	c.689G>A	p.Arg230Gln	missense_variant	Exon 5 of 8		NP_689928.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBCEL	ENST00000683345.1	c.689G>A	p.Arg230Gln	missense_variant	Exon 6 of 9		NM_001363644.2	ENSP00000507873.1
TBCEL-TECTA	ENST00000645041.1	c.641G>A	p.Arg214Gln	missense_variant	Exon 4 of 10			ENSP00000496315.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 247932 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457710 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724996

African (AFR) AF: 0.00 AC: 0 AN: 33270

American (AMR) AF: 0.0000225 AC: 1 AN: 44346

Ashkenazi Jewish (ASJ) AF: 0.0000769 AC: 2 AN: 26004

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.00 AC: 0 AN: 85532

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109868

Other (OTH) AF: 0.00 AC: 0 AN: 60178

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.689G>A (p.R230Q) alteration is located in exon 5 (coding exon 4) of the TBCEL gene. This alteration results from a G to A substitution at nucleotide position 689, causing the arginine (R) at amino acid position 230 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	Uncertain	0.095	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.046	T;T;T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.37	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.7	L;L;.;.
PhyloP100		6.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.6	N;N;N;.
REVEL	Benign	0.22
Sift	Benign	0.097	T;T;T;.
Sift4G	Uncertain	0.017	D;D;D;.
Polyphen		0.79	P;P;.;.
Vest4		0.43
MutPred		0.39		Loss of phosphorylation at S233 (P = 0.0613);Loss of phosphorylation at S233 (P = 0.0613);Loss of phosphorylation at S233 (P = 0.0613);.;
MVP		0.71
MPC		1.9
ClinPred		0.57	D
GERP RS		5.6
Varity_R		0.21
gMVP		0.63
Mutation Taster		=58/42	polymorphism

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

Other links and lift over

dbSNP: rs1457306216; hg19: chr11-120925994;