10-101131674-T-C

Variant names:

• chr10-101131674-T-C
• NM_005521.4:c.133T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005521.4(TLX1):​c.133T>C​(p.Tyr45His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TLX1 NM_005521.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.52

Genes affected

TLX1 (HGNC:5056): (T cell leukemia homeobox 1) This gene encodes a nuclear transcription factor that belongs to the NK-linked or NK-like (NKL) subfamily of homeobox genes. The encoded protein is required for normal development of the spleen during embryogenesis. This protein is also involved in specification of neuronal cell fates. Ectopic expression of this gene due to chromosomal translocations is associated with certain T-cell acute lymphoblastic leukemias. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2010]

TLX1NB (HGNC:37183): (TLX1 neighbor)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLX1	NM_005521.4	c.133T>C	p.Tyr45His	missense_variant	Exon 1 of 3	ENST00000370196.11	NP_005512.1
TLX1	NM_001195517.2	c.133T>C	p.Tyr45His	missense_variant	Exon 1 of 3		NP_001182446.1
TLX1	XM_011539744.4	c.133T>C	p.Tyr45His	missense_variant	Exon 1 of 3		XP_011538046.1
TLX1NB	NR_130724.1	n.580-4576A>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLX1	ENST00000370196.11	c.133T>C	p.Tyr45His	missense_variant	Exon 1 of 3	1	NM_005521.4	ENSP00000359215.6

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

Feb 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.133T>C (p.Y45H) alteration is located in exon 1 (coding exon 1) of the TLX1 gene. This alteration results from a T to C substitution at nucleotide position 133, causing the tyrosine (Y) at amino acid position 45 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	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T;T
M_CAP	Pathogenic	0.89	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.2	M;M
PhyloP100		4.5
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.34	N;N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.023	D;D
Sift4G	Benign	0.37	T;T
Polyphen		1.0	D;.
Vest4		0.62
MutPred		0.50		Loss of phosphorylation at Y45 (P = 0.0211);Loss of phosphorylation at Y45 (P = 0.0211);
MVP		0.93
ClinPred		0.95	D
GERP RS		4.6
PromoterAI		-0.016	Neutral
Varity_R		0.20
gMVP		0.57
Mutation Taster		=36/64	disease causing

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

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Other links and lift over

hg19: chr10-102891431;