10-101131777-C-T

Position:

• chr10-101131777-C-T

Variant summary

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

The NM_005521.4(TLX1):​c.236C>T​(p.Pro79Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000809 in 1,235,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
• Consequence: TLX1 NM_005521.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.656

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:):

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=0.23772857).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLX1	NM_005521.4	c.236C>T	p.Pro79Leu	missense_variant	1/3	ENST00000370196.11	NP_005512.1
TLX1	NM_001195517.2	c.236C>T	p.Pro79Leu	missense_variant	1/3		NP_001182446.1
TLX1	XM_011539744.4	c.236C>T	p.Pro79Leu	missense_variant	1/3		XP_011538046.1
TLX1NB	NR_130724.1	n.580-4679G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLX1	ENST00000370196.11	c.236C>T	p.Pro79Leu	missense_variant	1/3	1	NM_005521.4	ENSP00000359215	P1
TLX1	ENST00000467928.2	c.236C>T	p.Pro79Leu	missense_variant	1/3	1		ENSP00000434914
TLX1	ENST00000463716.3	c.50C>T	p.Pro17Leu	missense_variant	1/2	3		ENSP00000434358

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.09e-7 AC: 1 AN: 1235902 Hom.: 0 Cov.: 31 AF XY: 0.00000166 AC XY: 1 AN XY: 601296

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000361

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.: 32

Bravo AF: 0.00000378

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 22, 2022

The c.236C>T (p.P79L) alteration is located in exon 1 (coding exon 1) of the TLX1 gene. This alteration results from a C to T substitution at nucleotide position 236, causing the proline (P) at amino acid position 79 to be replaced by a leucine (L). 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	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.45	T;.;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.57	T;T;T
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.0	L;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.20	N;N;.
REVEL	Benign	0.24
Sift	Uncertain	0.0020	D;D;.
Sift4G	Benign	0.27	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.13
MutPred		0.25		Loss of relative solvent accessibility (P = 0.0404);Loss of relative solvent accessibility (P = 0.0404);.;
MVP		0.74
ClinPred		0.091	T
GERP RS		2.3
Varity_R		0.042
gMVP		0.35

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

Other links and lift over

dbSNP: rs1281113166; hg19: chr10-102891534;