11-121053659-G-A

Variant names:

• chr11-121053659-G-A
• rs767042196
• NM_001363644.2:c.382G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001363644.2(TBCEL):​c.382G>A​(p.Val128Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000657 in 1,612,204 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: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: TBCEL NM_001363644.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.34
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10930127).
• BS2: High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBCEL	NM_001363644.2	c.382G>A	p.Val128Ile	missense_variant	Exon 5 of 9	ENST00000683345.1	NP_001350573.1
TBCEL-TECTA	NM_001378761.1	c.382G>A	p.Val128Ile	missense_variant	Exon 4 of 30		NP_001365690.1
TBCEL	NM_001130047.3	c.382G>A	p.Val128Ile	missense_variant	Exon 4 of 8		NP_001123519.1
TBCEL	NM_152715.5	c.382G>A	p.Val128Ile	missense_variant	Exon 4 of 8		NP_689928.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBCEL	ENST00000683345.1	c.382G>A	p.Val128Ile	missense_variant	Exon 5 of 9		NM_001363644.2	ENSP00000507873.1
TBCEL-TECTA	ENST00000645041.1	c.334G>A	p.Val112Ile	missense_variant	Exon 3 of 10			ENSP00000496315.1

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151752 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000737

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 250704 AF XY: 0.0000295

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000678 AC: 99 AN: 1460452 Hom.: 0 Cov.: 31 AF XY: 0.0000729 AC XY: 53 AN XY: 726534

African (AFR) AF: 0.0000300 AC: 1 AN: 33386

American (AMR) AF: 0.0000224 AC: 1 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000855 AC: 95 AN: 1111120

Other (OTH) AF: 0.00 AC: 0 AN: 60296

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151752 Hom.: 0 Cov.: 32 AF XY: 0.0000675 AC XY: 5 AN XY: 74114

African (AFR) AF: 0.00 AC: 0 AN: 41360

American (AMR) AF: 0.00 AC: 0 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00316 AC: 1 AN: 316

European-Non Finnish (NFE) AF: 0.0000737 AC: 5 AN: 67860

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.382G>A (p.V128I) alteration is located in exon 4 (coding exon 3) of the TBCEL gene. This alteration results from a G to A substitution at nucleotide position 382, causing the valine (V) at amino acid position 128 to be replaced by an isoleucine (I). 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	0.079
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.55
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	T;T;T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	.;D;D;D
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.67	N;N;.;.
PhyloP100		4.3
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	0.46	N;N;N;.
REVEL	Benign	0.061
Sift	Benign	0.11	T;T;T;.
Sift4G	Benign	0.87	T;T;T;.
Polyphen		0.0040	B;B;.;.
Vest4		0.22
MutPred		0.46		Loss of catalytic residue at V128 (P = 0.0132);Loss of catalytic residue at V128 (P = 0.0132);Loss of catalytic residue at V128 (P = 0.0132);.;
MVP		0.26
MPC		0.61
ClinPred		0.11	T
GERP RS		6.0
Varity_R		0.035
gMVP		0.27
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs767042196; hg19: chr11-120924368;