16-1974227-G-T

Variant names:

• chr16-1974227-G-T
• rs375415353
• NM_006453.3:c.124G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006453.3(TBL3):​c.124G>T​(p.Val42Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TBL3 NM_006453.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.744

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28062034).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBL3	NM_006453.3	c.124G>T	p.Val42Phe	missense_variant	Exon 3 of 22	ENST00000568546.6	NP_006444.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBL3	ENST00000568546.6	c.124G>T	p.Val42Phe	missense_variant	Exon 3 of 22	1	NM_006453.3	ENSP00000454836.1
TBL3	ENST00000561907.5	n.140G>T		non_coding_transcript_exon_variant	Exon 3 of 6	2		ENSP00000454735.1
TBL3	ENST00000569628.5	n.292G>T		non_coding_transcript_exon_variant	Exon 2 of 21	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450546 Hom.: 0 Cov.: 36 AF XY: 0.00000139 AC XY: 1 AN XY: 720502

Gnomad4 AFR exome AF: 0.0000300

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: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Benign	0.90
DEOGEN2	Benign	0.040	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.9	N
Sift	Benign	0.047	D
Sift4G	Benign	0.14	T
Polyphen		0.71	P
Vest4		0.49
MutPred		0.66		Gain of sheet (P = 0.1539);
MVP		0.15
MPC		0.25
ClinPred		0.14	T
GERP RS		0.24
Varity_R		0.091
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs375415353; hg19: chr16-2024228;