dbSNP rs772569204: TBL3:p.Asp65Glu (chr16-1974381-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_006453.3(TBL3):c.195C>A(p.Asp65Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TBL3
NM_006453.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.689

Variant links:

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]

TBL3 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
TBL3	NM_006453.3 link	c.195C>A	p.Asp65Glu	missense_variant	Exon 4 of 22	ENST00000568546.6	NP_006444.2	Q12788

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TBL3	ENST00000568546.6 link	c.195C>A	p.Asp65Glu	missense_variant	Exon 4 of 22	1	NM_006453.3	ENSP00000454836.1	Q12788
TBL3	ENST00000561907.5 link	n.211C>A		non_coding_transcript_exon_variant	Exon 4 of 6	2		ENSP00000454735.1	H3BN88
TBL3	ENST00000569628.5 link	n.363C>A		non_coding_transcript_exon_variant	Exon 3 of 21	2
TBL3	ENST00000332704.5 link	c.-199C>A		upstream_gene_variant		1		ENSP00000331815.5	J3KNP2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

248092

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134026

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:

0.0000467

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457888

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725034

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:

0.0000189

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.014

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.022

Eigen

Benign

0.053

Eigen_PC

Benign

0.090

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.76

M_CAP

Benign

0.029

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.2

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.3

Sift

Benign

0.29

Sift4G

Benign

0.19

Polyphen

0.68

Vest4

0.46

MutPred

0.29

Loss of sheet (P = 0.0817);

MVP

0.52

MPC

0.18

ClinPred

0.26

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.049

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.25

Position offset: 4

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over