19-48493993-C-A

Position:

• chr19-48493993-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001388485.1(LMTK3):​c.3793G>T​(p.Ala1265Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 929,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: LMTK3 NM_001388485.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.712

Genes affected

LMTK3 (HGNC:19295): (lemur tyrosine kinase 3) Predicted to enable protein kinase activity. Predicted to be involved in protein phosphorylation. Predicted to be located in Golgi membrane; axon; and dendrite. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15757653).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMTK3	NM_001388485.1	c.3793G>T	p.Ala1265Ser	missense_variant	12/15	ENST00000600059.6	NP_001375414.1
LMTK3	NM_001080434.2	c.3793G>T	p.Ala1265Ser	missense_variant	13/16		NP_001073903.2
LMTK3	XM_011526411.3	c.3871G>T	p.Ala1291Ser	missense_variant	13/16		XP_011524713.1
LMTK3	XM_011526412.3	c.3838G>T	p.Ala1280Ser	missense_variant	13/16		XP_011524714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMTK3	ENST00000600059.6	c.3793G>T	p.Ala1265Ser	missense_variant	12/15	2	NM_001388485.1	ENSP00000472020.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000161 AC: 15 AN: 929036 Hom.: 0 Cov.: 30 AF XY: 0.0000114 AC XY: 5 AN XY: 438746

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: 0.0000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Nov 25, 2024

The c.3880G>T (p.A1294S) alteration is located in exon 13 (coding exon 13) of the LMTK3 gene. This alteration results from a G to T substitution at nucleotide position 3880, causing the alanine (A) at amino acid position 1294 to be replaced by a serine (S). 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	Benign	0.10
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0034	T;.;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.45	T;T;T
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.66	.;N;.
REVEL	Benign	0.061
Sift	Uncertain	0.0040	.;D;.
Sift4G	Benign	0.63	T;T;.
Polyphen		0.012	B;.;.
Vest4		0.19
MutPred		0.20		Gain of glycosylation at A1265 (P = 0.0024);.;.;
MVP		0.37
ClinPred		0.46	T
GERP RS		-0.14
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.3
Varity_R		0.080

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

LitVar

Other links and lift over

dbSNP: rs1972279424; hg19: chr19-48997250;