5-171309564-G-C

Variant names:

• chr5-171309564-G-C
• NM_021025.4:c.199G>C

Variant summary

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

The NM_021025.4(TLX3):​c.199G>C​(p.Gly67Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,433,414 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TLX3 NM_021025.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.21

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

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
TLX3	NM_021025.4	c.199G>C	p.Gly67Arg	missense_variant	Exon 1 of 3	ENST00000296921.6	NP_066305.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLX3	ENST00000296921.6	c.199G>C	p.Gly67Arg	missense_variant	Exon 1 of 3	1	NM_021025.4	ENSP00000296921.5
ENSG00000275038	ENST00000619056.2	n.214C>G		non_coding_transcript_exon_variant	Exon 1 of 2	6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1433414 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 710980

Gnomad4 AFR exome AF: 0.00

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: 9.10e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.199G>C (p.G67R) alteration is located in exon 1 (coding exon 1) of the TLX3 gene. This alteration results from a G to C substitution at nucleotide position 199, causing the glycine (G) at amino acid position 67 to be replaced by an arginine (R). 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	Uncertain	0.45
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.059
Eigen_PC	Benign	-0.060
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	-0.025	T
MutationAssessor	Benign	2.0	M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.25
Sift	Benign	0.096	T
Sift4G	Benign	0.30	T
Polyphen		0.86	P
Vest4		0.62
MutPred		0.33		Gain of methylation at G67 (P = 0.0643);
MVP		0.84
MPC		0.91
ClinPred		0.77	D
GERP RS		3.4
Varity_R		0.16
gMVP		0.64

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: chr5-170736568;