4-99885642-C-T

Variant summary

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

The NM_021970.4(LAMTOR3):​c.137G>A​(p.Arg46Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,613,090 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

LAMTOR3
NM_021970.4 missense

Scores

7
5
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.41
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LAMTOR3NM_021970.4 linkc.137G>A p.Arg46Gln missense_variant Exon 5 of 7 ENST00000499666.7 NP_068805.1 Q9UHA4-1
LAMTOR3NM_001243736.1 linkc.116G>A p.Arg39Gln missense_variant Exon 5 of 7 NP_001230665.1 Q9UHA4-2
LAMTOR3NR_024170.1 linkn.340G>A non_coding_transcript_exon_variant Exon 4 of 6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LAMTOR3ENST00000499666.7 linkc.137G>A p.Arg46Gln missense_variant Exon 5 of 7 1 NM_021970.4 ENSP00000424183.1 Q9UHA4-1
LAMTOR3ENST00000515100.1 linkn.222G>A non_coding_transcript_exon_variant Exon 4 of 6 1
LAMTOR3ENST00000226522.8 linkc.116G>A p.Arg39Gln missense_variant Exon 5 of 7 3 ENSP00000226522.8 Q9UHA4-2

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152126
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000279
AC:
7
AN:
250490
Hom.:
0
AF XY:
0.0000369
AC XY:
5
AN XY:
135452
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000617
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000240
AC:
35
AN:
1460964
Hom.:
0
Cov.:
30
AF XY:
0.0000206
AC XY:
15
AN XY:
726826
show subpopulations
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:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000288
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152126
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74298
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000135
Hom.:
0
Bravo
AF:
0.0000491
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000546
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 04, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.137G>A (p.R46Q) alteration is located in exon 5 (coding exon 4) of the LAMTOR3 gene. This alteration results from a G to A substitution at nucleotide position 137, causing the arginine (R) at amino acid position 46 to be replaced by a glutamine (Q). 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
0.89
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
31
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.056
T;.
Eigen
Uncertain
0.66
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Benign
0.016
T
MetaRNN
Uncertain
0.67
D;D
MetaSVM
Benign
-0.29
T
MutationAssessor
Uncertain
2.1
M;.
PrimateAI
Pathogenic
0.83
D
PROVEAN
Benign
-2.3
N;N
REVEL
Benign
0.19
Sift
Uncertain
0.014
D;T
Sift4G
Benign
0.11
T;T
Polyphen
1.0
D;.
Vest4
0.89
MVP
0.57
MPC
0.76
ClinPred
0.92
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.64
gMVP
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.16
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.

Other links and lift over

dbSNP: rs780467121; hg19: chr4-100806799; COSMIC: COSV99895989; API