10-101131952-C-A

Variant names:

• chr10-101131952-C-A
• NM_005521.4:c.411C>A

Variant summary

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

The NM_005521.4(TLX1):​c.411C>A​(p.His137Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000756 in 1,323,122 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: TLX1 NM_005521.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.86

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

Verdict is Uncertain_significance. Variant got 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.411C>A	p.His137Gln	missense_variant	Exon 1 of 3	ENST00000370196.11	NP_005512.1
TLX1	NM_001195517.2	c.411C>A	p.His137Gln	missense_variant	Exon 1 of 3		NP_001182446.1
TLX1	XM_011539744.4	c.411C>A	p.His137Gln	missense_variant	Exon 1 of 3		XP_011538046.1
TLX1NB	NR_130724.1	n.580-4854G>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLX1	ENST00000370196.11	c.411C>A	p.His137Gln	missense_variant	Exon 1 of 3	1	NM_005521.4	ENSP00000359215.6
TLX1	ENST00000467928.2	c.411C>A	p.His137Gln	missense_variant	Exon 1 of 3	1		ENSP00000434914.2
TLX1	ENST00000463716.3	c.225C>A	p.His75Gln	missense_variant	Exon 1 of 2	3		ENSP00000434358.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.56e-7 AC: 1 AN: 1323122 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 652710

Gnomad4 AFR exome AF: 0.0000368

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: 0.00

Gnomad4 OTH exome AF: 0.00

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 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.411C>A (p.H137Q) alteration is located in exon 1 (coding exon 1) of the TLX1 gene. This alteration results from a C to A substitution at nucleotide position 411, causing the histidine (H) at amino acid position 137 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	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D;.;.
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Uncertain	0.72	D;D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.1	M;M;.
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-4.7	D;D;.
REVEL	Pathogenic	0.70
Sift	Benign	0.053	T;D;.
Sift4G	Benign	0.092	T;T;D
Polyphen		0.97	D;.;.
Vest4		0.39
MutPred		0.26		Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);.;
MVP		0.92
ClinPred		0.99	D
GERP RS		2.5
Varity_R		0.40
gMVP		0.72

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: chr10-102891709;