Genetic Variant TBCA:p.Val6Leu (chr5-77776242-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004607.3(TBCA):c.16G>C(p.Val6Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000677 in 1,579,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict 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: 0.000070 ( 0 hom. )

Consequence

TBCA
NM_004607.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.13

Variant links:

Genes affected

TBCA (HGNC:11579): (tubulin folding cofactor A) The product of this gene is one of four proteins (cofactors A, D, E, and C) involved in the pathway leading to correctly folded beta-tubulin from folding intermediates. Cofactors A and D are believed to play a role in capturing and stabilizing beta-tubulin intermediates in a quasi-native confirmation. Cofactor E binds to the cofactor D/beta-tubulin complex; interaction with cofactor C then causes the release of beta-tubulin polypeptides that are committed to the native state. This gene encodes chaperonin cofactor A. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

TBCA links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.045512408).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBCA	NM_004607.3 link	c.16G>C	p.Val6Leu	missense_variant	Exon 1 of 4	ENST00000380377.9	NP_004598.1	O75347-1Q6FGD7
TBCA	NM_001297738.2 link	c.16G>C	p.Val6Leu	missense_variant	Exon 1 of 3		NP_001284667.1	O75347-2
TBCA	NM_001297740.2 link	c.16G>C	p.Val6Leu	missense_variant	Exon 1 of 3		NP_001284669.1	E5RIX8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBCA	ENST00000380377.9 link	c.16G>C	p.Val6Leu	missense_variant	Exon 1 of 4	1	NM_004607.3	ENSP00000369736.4		O75347-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000509

AC:

AN:

196624

Hom.:

AF XY:

0.0000190

AC XY:

AN XY:

105410

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:

0.000118

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000701

AC:

100

AN:

1427160

Hom.:

Cov.:

AF XY:

0.0000594

AC XY:

AN XY:

706816

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:

0.0000123

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000867

Gnomad4 OTH exome

AF:

0.0000678

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.0000654

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:

0.0000675

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000834

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.16G>C (p.V6L) alteration is located in exon 1 (coding exon 1) of the TBCA gene. This alteration results from a G to C substitution at nucleotide position 16, causing the valine (V) at amino acid position 6 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

0.11

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.013

T;.;T;.;T

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.52

LIST_S2

Uncertain

0.86

D;D;D;D;.

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.046

T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.0

N;N;.;.;.

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

0.17

N;N;N;N;D

REVEL

Benign

0.10

Sift

Benign

1.0

T;T;T;T;.

Sift4G

Benign

1.0

T;T;T;T;.

Polyphen

0.0

B;.;.;.;.

Vest4

0.12

MutPred

0.24

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

0.14

MPC

0.37

ClinPred

0.14

GERP RS

3.9

Varity_R

0.18

gMVP

0.52

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