chr19-48491421-C-A

Variant names:

• chr19-48491421-C-A
• NM_001388485.1:c.4211G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001388485.1(LMTK3):​c.4211G>T​(p.Ser1404Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000799 in 1,250,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/15 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.)
• Consequence: LMTK3 NM_001388485.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.735
• Publications: 0 publications found

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]

LMTK3 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36554748).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001388485.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMTK3	NM_001388485.1	MANE Select	c.4211G>T	p.Ser1404Ile	missense	Exon 13 of 15	NP_001375414.1	Q96Q04
	LMTK3	NM_001080434.2		c.4211G>T	p.Ser1404Ile	missense	Exon 14 of 16	NP_001073903.2	Q96Q04

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMTK3	ENST00000600059.6	TSL:2 MANE Select	c.4211G>T	p.Ser1404Ile	missense	Exon 13 of 15	ENSP00000472020.1	Q96Q04
	LMTK3	ENST00000650440.1		c.4289G>T	p.Ser1430Ile	missense	Exon 14 of 16	ENSP00000497480.1	A0A3B3ISL5
	LMTK3	ENST00000673139.1		c.4211G>T	p.Ser1404Ile	missense	Exon 14 of 16	ENSP00000500153.1	Q96Q04

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.99e-7 AC: 1 AN: 1250892 Hom.: 0 Cov.: 35 AF XY: 0.00000164 AC XY: 1 AN XY: 611234

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24258

American (AMR) AF: 0.00 AC: 0 AN: 16782

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18574

East Asian (EAS) AF: 0.00 AC: 0 AN: 26476

South Asian (SAS) AF: 0.00 AC: 0 AN: 61228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3904

European-Non Finnish (NFE) AF: 9.91e-7 AC: 1 AN: 1008720

Other (OTH) AF: 0.00 AC: 0 AN: 50664

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	0.98
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.32	N
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.37	T
PhyloP100		0.73
ClinPred		0.88	D
GERP RS		1.6
Varity_R		0.095
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

hg19: chr19-48994678;