Genetic Variant LAMTOR3:p.Pro31Ala (chr4-99887308-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_021970.4(LAMTOR3):c.91C>G(p.Pro31Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000708 in 1,413,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000071 ( 0 hom. )

Consequence

LAMTOR3
NM_021970.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.99

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.849

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021970.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LAMTOR3	NM_021970.4	MANE Select	c.91C>G	p.Pro31Ala	missense	Exon 4 of 7	NP_068805.1	Q9UHA4-1
LAMTOR3	NM_001243736.1		c.91C>G	p.Pro31Ala	missense	Exon 4 of 7	NP_001230665.1	Q9UHA4-2
LAMTOR3	NR_024170.1		n.294C>G		non_coding_transcript_exon	Exon 3 of 6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LAMTOR3	ENST00000499666.7	TSL:1 MANE Select	c.91C>G	p.Pro31Ala	missense	Exon 4 of 7	ENSP00000424183.1	Q9UHA4-1
LAMTOR3	ENST00000515100.1	TSL:1	n.176C>G		non_coding_transcript_exon	Exon 3 of 6
LAMTOR3	ENST00000871285.1		c.91C>G	p.Pro31Ala	missense	Exon 3 of 6	ENSP00000541344.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000445

AC:

AN:

224774

AF XY:

0.00000816

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000973

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000708

AC:

AN:

1413200

Hom.:

Cov.:

AF XY:

0.00000996

AC XY:

AN XY:

702852

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31204

American (AMR)

AF:

0.00

AC:

AN:

39786

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25210

East Asian (EAS)

AF:

0.00

AC:

AN:

36928

South Asian (SAS)

AF:

0.00

AC:

AN:

78694

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52312

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5640

European-Non Finnish (NFE)

AF:

0.00000922

AC:

AN:

1085084

Other (OTH)

AF:

0.00

AC:

AN:

58342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.430

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.018

MetaRNN

Pathogenic

0.85

MetaSVM

Uncertain

-0.19

MutationAssessor

Uncertain

2.6

PhyloP100

9.0

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-4.9

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0050

Sift4G

Benign

0.15

Polyphen

0.41

Vest4

0.84

MutPred

0.78

Gain of sheet (P = 0.0221)

MVP

0.43

MPC

0.25

ClinPred

0.99

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.56

gMVP

0.68

Mutation Taster

=27/73

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over