NM_006453.3:c.331C>T

Variant names:

• chr16-1974631-C-T
• rs867622714
• NM_006453.3:c.331C>T

Variant summary

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

The NM_006453.3(TBL3):​c.331C>T​(p.Pro111Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000823 in 1,457,688 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: TBL3 NM_006453.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.46

Genes affected

TBL3 (HGNC:11587): (transducin beta like 3) The protein encoded by this gene has sequence similarity with members of the WD40 repeat-containing protein family. The WD40 group is a large family of proteins, which appear to have a regulatory function. It is believed that the WD40 repeats mediate protein-protein interactions and members of the family are involved in signal transduction, RNA processing, gene regulation, vesicular trafficking, cytoskeletal assembly and may play a role in the control of cytotypic differentiation. This gene has multiple polyadenylation sites. It might have multiple alternatively spliced transcript variants but the variants have not been fully described yet. [provided by RefSeq, Jul 2008]

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
TBL3	NM_006453.3	c.331C>T	p.Pro111Ser	missense_variant	Exon 5 of 22	ENST00000568546.6	NP_006444.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBL3	ENST00000568546.6	c.331C>T	p.Pro111Ser	missense_variant	Exon 5 of 22	1	NM_006453.3	ENSP00000454836.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000823 AC: 12 AN: 1457688 Hom.: 0 Cov.: 36 AF XY: 0.0000124 AC XY: 9 AN XY: 724450

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 23, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.331C>T (p.P111S) alteration is located in exon 5 (coding exon 5) of the TBL3 gene. This alteration results from a C to T substitution at nucleotide position 331, causing the proline (P) at amino acid position 111 to be replaced by a serine (S). 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	0.38
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.4	L
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-7.0	D
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.051	T
Polyphen		1.0	D
Vest4		0.51
MutPred		0.64		Gain of glycosylation at P111 (P = 0.0475);
MVP		0.77
MPC		0.62
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.65

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

Other links and lift over

dbSNP: rs867622714; hg19: chr16-2024632;