5-171309462-C-G

Variant names:

• chr5-171309462-C-G
• rs199762968
• NM_021025.4:c.97C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021025.4(TLX3):​c.97C>G​(p.Pro33Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. P33S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TLX3 NM_021025.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.384
• Publications: 0 publications found

Genes affected

TLX3 (HGNC:13532): (T cell leukemia homeobox 3) The protein encoded by this gene is an orphan homeobox protein that encodes a DNA-binding nuclear transcription factor. A translocation [t(5;14)(q35;q32)] involving this gene is associated with T-cell acute lymphoblastic leukemia (T-ALL) in children and young adults. [provided by RefSeq, Nov 2015]

ENSG00000275038 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.063987255).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021025.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLX3	NM_021025.4	MANE Select	c.97C>G	p.Pro33Ala	missense	Exon 1 of 3	NP_066305.2	O43711

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLX3	ENST00000296921.6	TSL:1 MANE Select	c.97C>G	p.Pro33Ala	missense	Exon 1 of 3	ENSP00000296921.5	O43711
	ENSG00000275038	ENST00000619056.2	TSL:6	n.244+72G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1446668 Hom.: 0 Cov.: 37 AF XY: 0.00000139 AC XY: 1 AN XY: 719070

African (AFR) AF: 0.00 AC: 0 AN: 31996

American (AMR) AF: 0.00 AC: 0 AN: 43278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25712

East Asian (EAS) AF: 0.00 AC: 0 AN: 38614

South Asian (SAS) AF: 0.00 AC: 0 AN: 84962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51042

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5588

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1105824

Other (OTH) AF: 0.00 AC: 0 AN: 59652

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	13
DANN	Benign	0.88
DEOGEN2	Benign	0.30	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.51	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.38
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.14
Sift	Benign	0.86	T
Sift4G	Benign	0.84	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.19		Loss of glycosylation at P33 (P = 0.0596)
MVP		0.56
MPC		0.30
ClinPred		0.072	T
GERP RS		1.6
PromoterAI		0.073	Neutral
Varity_R		0.017
gMVP		0.31
Mutation Taster		=90/10	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

Other links and lift over

dbSNP: rs199762968; hg19: chr5-170736466;