NM_021970.4:c.29A>G

Variant names:

• chr4-99892015-T-C
• NM_021970.4:c.29A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021970.4(LAMTOR3):​c.29A>G​(p.Tyr10Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000282 in 1,419,340 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: LAMTOR3 NM_021970.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.02
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.29A>G	p.Tyr10Cys	missense	Exon 3 of 7	NP_068805.1	Q9UHA4-1
	LAMTOR3	NM_001243736.1		c.29A>G	p.Tyr10Cys	missense	Exon 3 of 7	NP_001230665.1	Q9UHA4-2
	LAMTOR3	NR_024170.1		n.232A>G		non_coding_transcript_exon	Exon 2 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMTOR3	ENST00000499666.7	TSL:1 MANE Select	c.29A>G	p.Tyr10Cys	missense	Exon 3 of 7	ENSP00000424183.1	Q9UHA4-1
	LAMTOR3	ENST00000515100.1	TSL:1	n.114A>G		non_coding_transcript_exon	Exon 2 of 6
	LAMTOR3	ENST00000871285.1		c.29A>G	p.Tyr10Cys	missense	Exon 2 of 6	ENSP00000541344.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000282 AC: 4 AN: 1419340 Hom.: 0 Cov.: 31 AF XY: 0.00000425 AC XY: 3 AN XY: 705866

African (AFR) AF: 0.00 AC: 0 AN: 30280

American (AMR) AF: 0.00 AC: 0 AN: 33674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24810

East Asian (EAS) AF: 0.00 AC: 0 AN: 37320

South Asian (SAS) AF: 0.00 AC: 0 AN: 78974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52882

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 0.00000365 AC: 4 AN: 1097268

Other (OTH) AF: 0.00 AC: 0 AN: 58478

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.6	L
PhyloP100		6.0
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.19
Sift	Benign	0.13	T
Sift4G	Benign	0.17	T
Polyphen		0.99	D
Vest4		0.61
MutPred		0.42		Gain of methylation at K11 (P = 0.0176)
MVP		0.29
MPC		0.48
ClinPred		0.95	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.78
Mutation Taster		=52/48	polymorphism

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

hg19: chr4-100813172;