16-1974832-C-T

Variant names:

• chr16-1974832-C-T
• rs199757463
• NM_006453.3:c.449C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006453.3(TBL3):​c.449C>T​(p.Ser150Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000601 in 1,613,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: TBL3 NM_006453.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.58
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32643494).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006453.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBL3	NM_006453.3	MANE Select	c.449C>T	p.Ser150Leu	missense	Exon 6 of 22	NP_006444.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBL3	ENST00000568546.6	TSL:1 MANE Select	c.449C>T	p.Ser150Leu	missense	Exon 6 of 22	ENSP00000454836.1	Q12788
	TBL3	ENST00000332704.5	TSL:1	c.170C>T	p.Ser57Leu	missense	Exon 2 of 18	ENSP00000331815.5	J3KNP2
	TBL3	ENST00000939205.1		c.449C>T	p.Ser150Leu	missense	Exon 6 of 22	ENSP00000609264.1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000128 AC: 32 AN: 250214 AF XY: 0.000111

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00279

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.0000602 AC: 88 AN: 1460882 Hom.: 0 Cov.: 36 AF XY: 0.0000482 AC XY: 35 AN XY: 726760

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00241 AC: 63 AN: 26124

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111944

Other (OTH) AF: 0.000182 AC: 11 AN: 60370

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152248 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74376

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000293 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.6
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.0	D
Sift	Benign	0.064	T
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.77
MutPred		0.50		Loss of disorder (P = 0.0122)
MVP		0.82
MPC		0.52
ClinPred		0.62	D
GERP RS		5.0
PromoterAI		0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.12
gMVP		0.65
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs199757463; hg19: chr16-2024833;