4-99884116-A-G

Position:

chr4-99884116-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The ENST00000499666.7(LAMTOR3):c.247T>C(p.Phe83Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,611,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

LAMTOR3
ENST00000499666.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.78

Variant links:

Genes affected

LAMTOR3 (HGNC:15606): (late endosomal/lysosomal adaptor, MAPK and MTOR activator 3) This gene encodes a scaffold protein that functions in the extracellular signal-regulated kinase (ERK) cascade. The protein is localized to late endosomes by the mitogen-activated protein-binding protein-interacting protein, and binds specifically to MAP kinase kinase MAP2K1/MEK1, MAP kinase MAPK3/ERK1, and MAP kinase MAPK1/ERK2. Studies of the orthologous gene in mouse indicate that it regulates late endosomal traffic and cell proliferation. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. A pseudogene of this gene is located on the long arm of chromosome 13. [provided by RefSeq, Aug 2011]

LAMTOR3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.35860425).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LAMTOR3	NM_021970.4 linkuse as main transcript	c.247T>C	p.Phe83Leu	missense_variant	6/7	ENST00000499666.7	NP_068805.1
LAMTOR3	NM_001243736.1 linkuse as main transcript	c.226T>C	p.Phe76Leu	missense_variant	6/7		NP_001230665.1
LAMTOR3	NR_024170.1 linkuse as main transcript	n.450T>C		non_coding_transcript_exon_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMTOR3	ENST00000499666.7 linkuse as main transcript	c.247T>C	p.Phe83Leu	missense_variant	6/7	1	NM_021970.4	ENSP00000424183	P1	Q9UHA4-1
LAMTOR3	ENST00000515100.1 linkuse as main transcript	n.332T>C		non_coding_transcript_exon_variant	5/6	1
LAMTOR3	ENST00000226522.8 linkuse as main transcript	c.226T>C	p.Phe76Leu	missense_variant	6/7	3		ENSP00000226522		Q9UHA4-2

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000195

AC:

AN:

251208

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00189

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000112

AC:

163

AN:

1459732

Hom.:

Cov.:

AF XY:

0.0000964

AC XY:

AN XY:

726362

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.00211

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000594

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000158

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.000957

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.000162

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2022

The c.247T>C (p.F83L) alteration is located in exon 6 (coding exon 5) of the LAMTOR3 gene. This alteration results from a T to C substitution at nucleotide position 247, causing the phenylalanine (F) at amino acid position 83 to be replaced by a leucine (L). 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

0.95

BayesDel_addAF

Uncertain

0.099

BayesDel_noAF

Pathogenic

0.21

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.021

T;.

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.0068

MetaRNN

Benign

0.36

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.9

L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-2.1

N;N

REVEL

Uncertain

0.52

Sift

Benign

0.15

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.65

P;.

Vest4

0.90

MutPred

0.68

Loss of sheet (P = 0.1158);.;

MVP

0.53

MPC

0.22

ClinPred

0.25

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.54

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over