chr19-39785698-A-T

Position:

• chr19-39785698-A-T

Variant summary

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

The NM_001382345.1(LEUTX):​c.160A>T​(p.Ile54Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,398,936 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LEUTX NM_001382345.1 missense, splice_region
• Scores: Splicing: ADA: 0.0005627
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.05

Genes affected

LEUTX (HGNC:31953): (leucine twenty homeobox) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

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/exons	MANE	Protein	UniProt
LEUTX	NM_001382345.1	c.160A>T	p.Ile54Phe	missense_variant, splice_region_variant	3/3	ENST00000638280.2	NP_001369274.1
LEUTX	NM_001143832.2	c.70A>T	p.Ile24Phe	missense_variant, splice_region_variant	3/3		NP_001137304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LEUTX	ENST00000638280.2	c.160A>T	p.Ile54Phe	missense_variant, splice_region_variant	3/3	3	NM_001382345.1	ENSP00000491740.1
LEUTX	ENST00000396841.4	c.70A>T	p.Ile24Phe	missense_variant, splice_region_variant	3/3	2		ENSP00000380053.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1398936 Hom.: 0 Cov.: 31 AF XY: 0.00000435 AC XY: 3 AN XY: 689956

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: 0.00000278

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2023

The c.70A>T (p.I24F) alteration is located in exon 3 (coding exon 2) of the LEUTX gene. This alteration results from a A to T substitution at nucleotide position 70, causing the isoleucine (I) at amino acid position 24 to be replaced by a phenylalanine (F). 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	0.75
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	17
DANN	Benign	0.78
DEOGEN2	Pathogenic	0.84	D;.
Eigen	Benign	-0.080
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.086	N
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.5	D;.
REVEL	Uncertain	0.45
Sift	Uncertain	0.011	D;.
Sift4G	Uncertain	0.034	D;.
Polyphen		0.94	P;.
Vest4		0.44
MutPred		0.58		Loss of sheet (P = 0.0181);.;
MVP		0.37
ClinPred		0.31	T
GERP RS		1.5
Varity_R		0.26
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00056
dbscSNV1_RF	Benign	0.012
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: chr19-40276338;