4-99887308-G-A

Variant names:

• chr4-99887308-G-A
• rs1448741915
• NM_021970.4:c.91C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_021970.4(LAMTOR3):​c.91C>T​(p.Pro31Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. P31A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LAMTOR3 NM_021970.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.99
• Publications: 0 publications found

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]

ACMG classification

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, 0.881

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMTOR3	NM_021970.4	MANE Select	c.91C>T	p.Pro31Ser	missense	Exon 4 of 7	NP_068805.1	Q9UHA4-1
	LAMTOR3	NM_001243736.1		c.91C>T	p.Pro31Ser	missense	Exon 4 of 7	NP_001230665.1	Q9UHA4-2
	LAMTOR3	NR_024170.1		n.294C>T		non_coding_transcript_exon	Exon 3 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMTOR3	ENST00000499666.7	TSL:1 MANE Select	c.91C>T	p.Pro31Ser	missense	Exon 4 of 7	ENSP00000424183.1	Q9UHA4-1
	LAMTOR3	ENST00000515100.1	TSL:1	n.176C>T		non_coding_transcript_exon	Exon 3 of 6
	LAMTOR3	ENST00000871285.1		c.91C>T	p.Pro31Ser	missense	Exon 3 of 6	ENSP00000541344.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000445 AC: 1 AN: 224774 AF XY: 0.00

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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1413200 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 702852

African (AFR) AF: 0.00 AC: 0 AN: 31204

American (AMR) AF: 0.00 AC: 0 AN: 39786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25210

East Asian (EAS) AF: 0.00 AC: 0 AN: 36928

South Asian (SAS) AF: 0.00 AC: 0 AN: 78694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5640

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085084

Other (OTH) AF: 0.00 AC: 0 AN: 58342

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		9.0
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.055	T
Polyphen		0.89	P
Vest4		0.90
MutPred		0.81		Loss of methylation at K34 (P = 0.0692)
MVP		0.45
MPC		0.47
ClinPred		0.98	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.76
Mutation Taster		=32/68	disease causing

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

dbSNP: rs1448741915; hg19: chr4-100808465;