19-48493921-C-T

Variant names:

• chr19-48493921-C-T
• rs1972276787
• NM_001388485.1:c.3865G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001388485.1(LMTK3):​c.3865G>A​(p.Glu1289Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000113 in 882,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: LMTK3 NM_001388485.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.87

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32508385).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMTK3	NM_001388485.1	c.3865G>A	p.Glu1289Lys	missense_variant	Exon 12 of 15	ENST00000600059.6	NP_001375414.1
LMTK3	NM_001080434.2	c.3865G>A	p.Glu1289Lys	missense_variant	Exon 13 of 16		NP_001073903.2
LMTK3	XM_011526411.3	c.3943G>A	p.Glu1315Lys	missense_variant	Exon 13 of 16		XP_011524713.1
LMTK3	XM_011526412.3	c.3910G>A	p.Glu1304Lys	missense_variant	Exon 13 of 16		XP_011524714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMTK3	ENST00000600059.6	c.3865G>A	p.Glu1289Lys	missense_variant	Exon 12 of 15	2	NM_001388485.1	ENSP00000472020.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000113 AC: 1 AN: 882778 Hom.: 0 Cov.: 30 AF XY: 0.00000241 AC XY: 1 AN XY: 414730

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: 0.00000125

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

Dec 14, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3952G>A (p.E1318K) alteration is located in exon 13 (coding exon 13) of the LMTK3 gene. This alteration results from a G to A substitution at nucleotide position 3952, causing the glutamic acid (E) at amino acid position 1318 to be replaced by a lysine (K). 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	0.19
BayesDel_addAF	Benign	-0.0083	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T;.;.
Eigen	Benign	-0.0080
Eigen_PC	Benign	0.054
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.54	T;T;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.69	N;.;.
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-1.8	.;N;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.016	.;D;.
Sift4G	Benign	0.67	T;T;.
Polyphen		0.92	P;.;.
Vest4		0.30
MutPred		0.10		Gain of glycosylation at E1289 (P = 0.0123);.;.;
MVP		0.64
ClinPred		0.82	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16

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: rs1972276787; hg19: chr19-48997178;