10-101131665-G-A

Variant names:

• chr10-101131665-G-A
• rs1467334612
• NM_005521.4:c.124G>A

Variant summary

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

The NM_005521.4(TLX1):​c.124G>A​(p.Asp42Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,408,854 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D42Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TLX1 NM_005521.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.10

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.124G>A	p.Asp42Asn	missense_variant	Exon 1 of 3	ENST00000370196.11	NP_005512.1
TLX1	NM_001195517.2	c.124G>A	p.Asp42Asn	missense_variant	Exon 1 of 3		NP_001182446.1
TLX1	XM_011539744.4	c.124G>A	p.Asp42Asn	missense_variant	Exon 1 of 3		XP_011538046.1
TLX1NB	NR_130724.1	n.580-4567C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLX1	ENST00000370196.11	c.124G>A	p.Asp42Asn	missense_variant	Exon 1 of 3	1	NM_005521.4	ENSP00000359215.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1408854 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 700564

African (AFR) AF: 0.00 AC: 0 AN: 28546

American (AMR) AF: 0.00 AC: 0 AN: 37260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23716

East Asian (EAS) AF: 0.00 AC: 0 AN: 34098

South Asian (SAS) AF: 0.00 AC: 0 AN: 80034

European-Finnish (FIN) AF: 0.0000196 AC: 1 AN: 51096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5574

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090516

Other (OTH) AF: 0.0000172 AC: 1 AN: 58014

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.92	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.1	M;M
PhyloP100		9.1
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.95	N;N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.13	T;T
Polyphen		0.96	D;.
Vest4		0.27
MutPred		0.24		Loss of phosphorylation at Y45 (P = 0.0871);Loss of phosphorylation at Y45 (P = 0.0871);
MVP		0.93
ClinPred		0.94	D
GERP RS		4.6
PromoterAI		0.027	Neutral
Varity_R		0.30
gMVP		0.27
Mutation Taster		=62/38	polymorphism

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

dbSNP: rs1467334612; hg19: chr10-102891422;