4-99892015-T-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMTOR3	NM_021970.4	c.29A>G	p.Tyr10Cys	missense_variant	Exon 3 of 7	ENST00000499666.7	NP_068805.1
LAMTOR3	NM_001243736.1	c.29A>G	p.Tyr10Cys	missense_variant	Exon 3 of 7		NP_001230665.1
LAMTOR3	NR_024170.1	n.232A>G		non_coding_transcript_exon_variant	Exon 2 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMTOR3	ENST00000499666.7	c.29A>G	p.Tyr10Cys	missense_variant	Exon 3 of 7	1	NM_021970.4	ENSP00000424183.1
LAMTOR3	ENST00000515100.1	n.114A>G		non_coding_transcript_exon_variant	Exon 2 of 6	1
LAMTOR3	ENST00000226522.8	c.29A>G	p.Tyr10Cys	missense_variant	Exon 3 of 7	3		ENSP00000226522.8

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000365

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 04, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.29A>G (p.Y10C) alteration is located in exon 3 (coding exon 2) of the LAMTOR3 gene. This alteration results from a A to G substitution at nucleotide position 29, causing the tyrosine (Y) at amino acid position 10 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.19
Sift	Benign	0.13	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.99	D;.
Vest4		0.61
MutPred		0.42		Gain of methylation at K11 (P = 0.0176);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

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-100813172;