14-95691298-T-C

Position:

• chr14-95691298-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004918.4(TCL1B):​c.364T>C​(p.Tyr122His) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TCL1B NM_004918.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.07

Genes affected

TCL1B (HGNC:11649): (TCL1 family AKT coactivator B) Enables protein kinase binding activity and protein serine/threonine kinase activator activity. Involved in positive regulation of peptidyl-serine phosphorylation and positive regulation of protein serine/threonine kinase activity. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23162517).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCL1B	NM_004918.4	c.364T>C	p.Tyr122His	missense_variant	3/4	ENST00000340722.8	NP_004909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCL1B	ENST00000340722.8	c.364T>C	p.Tyr122His	missense_variant	3/4	1	NM_004918.4	ENSP00000343223	P1
TCL1B	ENST00000464815.5	n.394T>C		non_coding_transcript_exon_variant	3/3	1
TCL1B	ENST00000556665.1	n.324T>C		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Apr 06, 2022

The c.364T>C (p.Y122H) alteration is located in exon 3 (coding exon 3) of the TCL1B gene. This alteration results from a T to C substitution at nucleotide position 364, causing the tyrosine (Y) at amino acid position 122 to be replaced by a histidine (H). 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	0.24
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	5.1
DANN	Benign	0.95
DEOGEN2	Benign	0.0088	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.00085	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.055
Sift	Benign	0.42	T
Sift4G	Benign	0.51	T
Polyphen		0.83	P
Vest4		0.15
MutPred		0.70		Gain of disorder (P = 0.0287);
MVP		0.099
MPC		0.53
ClinPred		0.10	T
GERP RS		0.27
Varity_R		0.057
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1885880093; hg19: chr14-96157635;