Variant 14-95714032-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_021966.3(TCL1A):c.35C>T(p.Thr12Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

TCL1A
NM_021966.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.141

Variant links:

Genes affected

TCL1A (HGNC:11648): (TCL1 family AKT coactivator A) Overexpression of the TCL1 gene in humans has been implicated in the development of mature T cell leukemia, in which chromosomal rearrangements bring the TCL1 gene in close proximity to the T-cell antigen receptor (TCR)-alpha (MIM 186880) or TCR-beta (MIM 186930) regulatory elements (summarized by Virgilio et al., 1998 [PubMed 9520462]). In normal T cells TCL1 is expressed in CD4-/CD8- cells, but not in cells at later stages of differentiation. TCL1 functions as a coactivator of the cell survival kinase AKT (MIM 164730) (Laine et al., 2000 [PubMed 10983986]).[supplied by OMIM, Jul 2010]

TCL1A links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.2778713).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TCL1A	NM_021966.3 linkuse as main transcript	c.35C>T	p.Thr12Ile	missense_variant	1/4	ENST00000402399.6
TCL1A	NM_001098725.2 linkuse as main transcript	c.35C>T	p.Thr12Ile	missense_variant	1/4
TCL1A	NR_049726.2 linkuse as main transcript	n.94C>T		non_coding_transcript_exon_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCL1A	ENST00000402399.6 linkuse as main transcript	c.35C>T	p.Thr12Ile	missense_variant	1/4	1	NM_021966.3	P1
	ENST00000547644.6 linkuse as main transcript	n.152+2134G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

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

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249964

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135294

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:

0.00

Gnomad NFE exome

AF:

0.00000890

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461736

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727194

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:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2022

The c.35C>T (p.T12I) alteration is located in exon 1 (coding exon 1) of the TCL1A gene. This alteration results from a C to T substitution at nucleotide position 35, causing the threonine (T) at amino acid position 12 to be replaced by an isoleucine (I). 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

Benign

0.19

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

4.6

DANN

Benign

0.96

DEOGEN2

Benign

0.26

T;T;T;T

Eigen

Benign

-0.81

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.013

M_CAP

Benign

0.012

MetaRNN

Benign

0.28

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.5

L;L;L;L

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.7

N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.041

D;D;D;D

Sift4G

Uncertain

0.046

D;D;D;D

Polyphen

0.94

P;P;P;P

Vest4

0.18

MutPred

0.55

Loss of disorder (P = 0.0411);Loss of disorder (P = 0.0411);Loss of disorder (P = 0.0411);Loss of disorder (P = 0.0411);

MVP

0.33

MPC

0.36

ClinPred

0.16

GERP RS

-4.2

Varity_R

0.25

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over