3-186555051-C-T

Variant names:

• chr3-186555051-C-T
• rs775319222
• NM_018138.5:c.893G>A

Variant summary

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

The NM_018138.5(TBCCD1):​c.893G>A​(p.Cys298Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,266 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TBCCD1 NM_018138.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

Genes affected

TBCCD1 (HGNC:25546): (TBCC domain containing 1) Involved in several processes, including maintenance of Golgi location; maintenance of centrosome location; and regulation of cell shape. Located in spindle pole centrosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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
TBCCD1	NM_018138.5	c.893G>A	p.Cys298Tyr	missense_variant	Exon 5 of 8	ENST00000338733.10	NP_060608.1
TBCCD1	NM_001134415.1	c.893G>A	p.Cys298Tyr	missense_variant	Exon 5 of 8		NP_001127887.1
TBCCD1	NM_001286749.2	c.605G>A	p.Cys202Tyr	missense_variant	Exon 4 of 7		NP_001273678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBCCD1	ENST00000338733.10	c.893G>A	p.Cys298Tyr	missense_variant	Exon 5 of 8	1	NM_018138.5	ENSP00000341652.5
TBCCD1	ENST00000424280.5	c.893G>A	p.Cys298Tyr	missense_variant	Exon 5 of 8	5		ENSP00000411253.1
TBCCD1	ENST00000446782.5	c.605G>A	p.Cys202Tyr	missense_variant	Exon 4 of 7	2		ENSP00000397091.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000807 AC: 2 AN: 247724 Hom.: 0 AF XY: 0.00000747 AC XY: 1 AN XY: 133874

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: 0.0000673

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458266 Hom.: 0 Cov.: 32 AF XY: 0.00000414 AC XY: 3 AN XY: 725294

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: 0.0000468

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.893G>A (p.C298Y) alteration is located in exon 5 (coding exon 4) of the TBCCD1 gene. This alteration results from a G to A substitution at nucleotide position 893, causing the cysteine (C) at amino acid position 298 to be replaced by a tyrosine (Y). 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	0.41
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T;.
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;.;D
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.72	D;D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.3	M;M;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Uncertain	0.46
Sift	Benign	0.046	D;D;D
Sift4G	Uncertain	0.054	T;T;D
Polyphen		0.98	D;D;.
Vest4		0.69
MutPred		0.44		Loss of catalytic residue at T300 (P = 0.0658);Loss of catalytic residue at T300 (P = 0.0658);.;
MVP		0.82
MPC		0.69
ClinPred		0.90	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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

Other links and lift over

dbSNP: rs775319222; hg19: chr3-186272840;