NM_021970.4:c.152C>T

Variant names:

• chr4-99885627-G-A
• rs1724908686
• NM_021970.4:c.152C>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.152C>T​(p.Ser51Phe) 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. S51Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LAMTOR3 NM_021970.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.40
• 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, 0.846

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.152C>T	p.Ser51Phe	missense	Exon 5 of 7	NP_068805.1	Q9UHA4-1
	LAMTOR3	NM_001243736.1		c.131C>T	p.Ser44Phe	missense	Exon 5 of 7	NP_001230665.1	Q9UHA4-2
	LAMTOR3	NR_024170.1		n.355C>T		non_coding_transcript_exon	Exon 4 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMTOR3	ENST00000499666.7	TSL:1 MANE Select	c.152C>T	p.Ser51Phe	missense	Exon 5 of 7	ENSP00000424183.1	Q9UHA4-1
	LAMTOR3	ENST00000515100.1	TSL:1	n.237C>T		non_coding_transcript_exon	Exon 4 of 6
	LAMTOR3	ENST00000871285.1		c.152C>T	p.Ser51Phe	missense	Exon 4 of 6	ENSP00000541344.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.085	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.4
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.014	D
Polyphen		0.99	D
Vest4		0.97
MutPred		0.57		Loss of catalytic residue at S51 (P = 0.0869)
MVP		0.64
MPC		0.67
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.77
gMVP		0.90
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1724908686; hg19: chr4-100806784;