19-48491505-G-C

Position:

• chr19-48491505-G-C

Variant summary

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

The NM_001388485.1(LMTK3):​c.4127C>G​(p.Pro1376Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 8.0e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LMTK3 NM_001388485.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.691

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=0.22580826).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMTK3	NM_001388485.1	c.4127C>G	p.Pro1376Arg	missense_variant	13/15	ENST00000600059.6
LMTK3	NM_001080434.2	c.4127C>G	p.Pro1376Arg	missense_variant	14/16
LMTK3	XM_011526411.3	c.4205C>G	p.Pro1402Arg	missense_variant	14/16
LMTK3	XM_011526412.3	c.4172C>G	p.Pro1391Arg	missense_variant	14/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMTK3	ENST00000600059.6	c.4127C>G	p.Pro1376Arg	missense_variant	13/15	2	NM_001388485.1	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.96e-7 AC: 1 AN: 1256610 Hom.: 0 Cov.: 33 AF XY: 0.00000164 AC XY: 1 AN XY: 610888

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: 9.90e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000227

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

Aug 12, 2021

The c.4214C>G (p.P1405R) alteration is located in exon 14 (coding exon 14) of the LMTK3 gene. This alteration results from a C to G substitution at nucleotide position 4214, causing the proline (P) at amino acid position 1405 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	Benign	0.18
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0060	T;.;.
Eigen	Benign	-0.084
Eigen_PC	Benign	0.020
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.55	T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.0	L;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.86	D
Sift4G	Benign	0.083	T;T;.
Polyphen		0.62	P;.;.
Vest4		0.35
MutPred		0.24		Gain of solvent accessibility (P = 0.0971);.;.;
MVP		0.56
ClinPred		0.37	T
GERP RS		3.5
Varity_R		0.069

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: rs753831665; hg19: chr19-48994762;