Genetic Variant TBCB:p.Val161Leu (chr19-36121652-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001281.3(TBCB):c.481G>T(p.Val161Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000327 in 1,561,028 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

TBCB
NM_001281.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.17

Variant links:

Genes affected

TBCB (HGNC:1989): (tubulin folding cofactor B) Predicted to be involved in cell differentiation and nervous system development. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

TBCB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBCB	NM_001281.3 link	c.481G>T	p.Val161Leu	missense_variant	Exon 4 of 6	ENST00000221855.8	NP_001272.2	Q99426-1
TBCB	NM_001300971.3 link	c.328G>T	p.Val110Leu	missense_variant	Exon 4 of 6		NP_001287900.1	Q99426-2
TBCB	NR_155756.2 link	n.1075G>T		non_coding_transcript_exon_variant	Exon 4 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBCB	ENST00000221855.8 link	c.481G>T	p.Val161Leu	missense_variant	Exon 4 of 6	1	NM_001281.3	ENSP00000221855.3		Q99426-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000618

AC:

AN:

161762

Hom.:

AF XY:

0.0000114

AC XY:

AN XY:

88054

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000156

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000334

AC:

AN:

1408830

Hom.:

Cov.:

AF XY:

0.0000302

AC XY:

AN XY:

696438

show subpopulations

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:

0.0000405

Gnomad4 OTH exome

AF:

0.0000515

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000571

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.481G>T (p.V161L) alteration is located in exon 4 (coding exon 4) of the TBCB gene. This alteration results from a G to T substitution at nucleotide position 481, causing the valine (V) at amino acid position 161 to be replaced by a leucine (L). 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

0.16

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;T;T;.

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.85

D;D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.67

D;D;D;D

MetaSVM

Uncertain

0.37

MutationAssessor

Uncertain

2.5

M;.;.;.

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.4

N;.;.;.

REVEL

Uncertain

0.63

Sift

Benign

0.11

T;.;.;.

Sift4G

Benign

0.16

T;T;T;T

Polyphen

0.047

B;.;.;.

Vest4

0.61

MutPred

0.64

Loss of glycosylation at S158 (P = 0.0962);Loss of glycosylation at S158 (P = 0.0962);.;.;

MVP

0.88

MPC

0.72

ClinPred

0.87

GERP RS

4.2

Varity_R

0.12

gMVP

0.48

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over