Genetic Variant NM_014017.4:c.43A>G (chr1-156054932-A-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_014017.4(LAMTOR2):c.43A>G(p.Asn15Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N15H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LAMTOR2
NM_014017.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.60

Variant links:

Genes affected

LAMTOR2 (HGNC:29796): (late endosomal/lysosomal adaptor, MAPK and MTOR activator 2) The product of this gene is highly conserved with a mouse protein associated with the cytoplasmic face of late endosomes and lysosomes. The mouse protein interacts with MAPK scaffold protein 1, a component of the mitogen-activated protein kinase pathway. In humans, a mutation in this gene has been associated with a primary immunodeficiency syndrome, and suggests a role for this protein in endosomal biogenesis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2009]

LAMTOR2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMTOR2	NM_014017.4 link	c.43A>G	p.Asn15Asp	missense_variant	Exon 1 of 4	ENST00000368305.9	NP_054736.1	Q9Y2Q5-1
LAMTOR2	NM_001145264.2 link	c.43A>G	p.Asn15Asp	missense_variant	Exon 1 of 3		NP_001138736.1	Q9Y2Q5-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMTOR2	ENST00000368305.9 link	c.43A>G	p.Asn15Asp	missense_variant	Exon 1 of 4	1	NM_014017.4	ENSP00000357288.4		Q9Y2Q5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248942

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135126

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:

0.00000893

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460646

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726638

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Benign

-0.38

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;.;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.025

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.9

M;M;M

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.9

D;D;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.0030

D;T;D

Sift4G

Benign

0.11

T;D;D

Polyphen

0.99

D;.;.

Vest4

0.72

MutPred

0.70

Loss of MoRF binding (P = 0.0861);Loss of MoRF binding (P = 0.0861);Loss of MoRF binding (P = 0.0861);

MVP

0.37

MPC

2.4

ClinPred

0.99

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.87

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over