chr14-95713979-T-G

Position:

• chr14-95713979-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_021966.3(TCL1A):​c.88A>C​(p.Lys30Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: TCL1A NM_021966.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.657

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a mutagenesis_site Slightly reduced binding to AKT2. (size 0) in uniprot entity TCL1A_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06523523).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCL1A	NM_021966.3	c.88A>C	p.Lys30Gln	missense_variant	1/4	ENST00000402399.6
TCL1A	NM_001098725.2	c.88A>C	p.Lys30Gln	missense_variant	1/4
TCL1A	NR_049726.2	n.147A>C		non_coding_transcript_exon_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCL1A	ENST00000402399.6	c.88A>C	p.Lys30Gln	missense_variant	1/4	1	NM_021966.3	P1
	ENST00000547644.6	n.152+2081T>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2024

The c.88A>C (p.K30Q) alteration is located in exon 1 (coding exon 1) of the TCL1A gene. This alteration results from a A to C substitution at nucleotide position 88, causing the lysine (K) at amino acid position 30 to be replaced by a glutamine (Q). 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	0.10
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	1.5
DANN	Benign	0.63
DEOGEN2	Benign	0.13	T;T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0080	N
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.065	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.38	N;N;N;N
REVEL	Benign	0.019
Sift	Benign	0.45	T;T;T;T
Sift4G	Benign	0.35	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.11
MutPred		0.34		Loss of methylation at K30 (P = 0.0127);Loss of methylation at K30 (P = 0.0127);Loss of methylation at K30 (P = 0.0127);Loss of methylation at K30 (P = 0.0127);
MVP		0.37
MPC		0.27
ClinPred		0.13	T
GERP RS		0.42
Varity_R		0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-96180316;