4-99887337-G-T

Variant names:

• chr4-99887337-G-T
• rs745593345
• NM_021970.4:c.62C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_021970.4(LAMTOR3):​c.62C>A​(p.Ala21Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,383,832 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. A21G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: LAMTOR3 NM_021970.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.99

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMTOR3	NM_021970.4	c.62C>A	p.Ala21Asp	missense_variant	Exon 4 of 7	ENST00000499666.7	NP_068805.1
LAMTOR3	NM_001243736.1	c.62C>A	p.Ala21Asp	missense_variant	Exon 4 of 7		NP_001230665.1
LAMTOR3	NR_024170.1	n.265C>A		non_coding_transcript_exon_variant	Exon 3 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMTOR3	ENST00000499666.7	c.62C>A	p.Ala21Asp	missense_variant	Exon 4 of 7	1	NM_021970.4	ENSP00000424183.1
LAMTOR3	ENST00000515100.1	n.147C>A		non_coding_transcript_exon_variant	Exon 3 of 6	1
LAMTOR3	ENST00000226522.8	c.62C>A	p.Ala21Asp	missense_variant	Exon 4 of 7	3		ENSP00000226522.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000914 AC: 2 AN: 218890 Hom.: 0 AF XY: 0.00000837 AC XY: 1 AN XY: 119476

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000665

Gnomad SAS exome AF: 0.0000377

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1383832 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 688068

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000273

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	-0.055	T
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.015	D;D
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.66		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.63
MPC		0.89
ClinPred		0.90	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.94

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

Other links and lift over

dbSNP: rs745593345; hg19: chr4-100808494;