NM_005521.4:c.434C>G

Variant names:

• chr10-101131975-C-G
• rs200573821
• NM_005521.4:c.434C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005521.4(TLX1):​c.434C>G​(p.Ala145Gly) 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. 14/22 in silico tools predict a benign outcome for this variant. 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. A145V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TLX1 NM_005521.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.33

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19991061).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLX1	NM_005521.4	c.434C>G	p.Ala145Gly	missense_variant	Exon 1 of 3	ENST00000370196.11	NP_005512.1
TLX1	NM_001195517.2	c.434C>G	p.Ala145Gly	missense_variant	Exon 1 of 3		NP_001182446.1
TLX1	XM_011539744.4	c.434C>G	p.Ala145Gly	missense_variant	Exon 1 of 3		XP_011538046.1
TLX1NB	NR_130724.1	n.580-4877G>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLX1	ENST00000370196.11	c.434C>G	p.Ala145Gly	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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T;.;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.63	T;T;T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.1	L;L;.
PhyloP100		2.3
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.090	N;N;.
REVEL	Benign	0.17
Sift	Benign	0.30	T;T;.
Sift4G	Benign	0.42	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.11
MutPred		0.22		Gain of catalytic residue at L150 (P = 0.1695);Gain of catalytic residue at L150 (P = 0.1695);.;
MVP		0.88
ClinPred		0.26	T
GERP RS		4.2
PromoterAI		0.015	Neutral
Varity_R		0.14
gMVP		0.16
Mutation Taster		=74/26	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: rs200573821; hg19: chr10-102891732;