chr6-42745305-C-T

Variant names:

• chr6-42745305-C-T
• NM_003192.3:c.769G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003192.3(TBCC):​c.769G>A​(p.Ala257Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TBCC NM_003192.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.35

Genes affected

TBCC (HGNC:11580): (tubulin folding cofactor C) Cofactor C 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. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBCC	NM_003192.3	c.769G>A	p.Ala257Thr	missense_variant	Exon 1 of 1	ENST00000372876.2	NP_003183.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBCC	ENST00000372876.2	c.769G>A	p.Ala257Thr	missense_variant	Exon 1 of 1	6	NM_003192.3	ENSP00000361967.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.769G>A (p.A257T) alteration is located in exon 1 (coding exon 1) of the TBCC gene. This alteration results from a G to A substitution at nucleotide position 769, causing the alanine (A) at amino acid position 257 to be replaced by a threonine (T). 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	0.46
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.046	D
Polyphen		0.91	P
Vest4		0.51
MutPred		0.85		Gain of sheet (P = 0.1208);
MVP		0.82
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-42713043;