chr1-156054954-C-T

Variant names:

• chr1-156054954-C-T
• rs751699653
• NM_014017.4:c.65C>T

Variant summary

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

The NM_014017.4(LAMTOR2):​c.65C>T​(p.Thr22Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,459,696 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T22T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LAMTOR2 NM_014017.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.31
• Publications: 2 publications found

Genes affected

LAMTOR2 (HGNC:29796): (late endosomal/lysosomal adaptor, MAPK and MTOR activator 2) The product of this gene is highly conserved with a mouse protein associated with the cytoplasmic face of late endosomes and lysosomes. The mouse protein interacts with MAPK scaffold protein 1, a component of the mitogen-activated protein kinase pathway. In humans, a mutation in this gene has been associated with a primary immunodeficiency syndrome, and suggests a role for this protein in endosomal biogenesis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2009]

LAMTOR2 Gene-Disease associations (from GenCC):

• primary immunodeficiency syndrome due to p14 deficiency

  Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

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_014017.4. 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
	LAMTOR2	NM_014017.4	MANE Select	c.65C>T	p.Thr22Ile	missense	Exon 1 of 4	NP_054736.1	Q9Y2Q5-1
	LAMTOR2	NM_001145264.2		c.65C>T	p.Thr22Ile	missense	Exon 1 of 3	NP_001138736.1	Q9Y2Q5-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMTOR2	ENST00000368305.9	TSL:1 MANE Select	c.65C>T	p.Thr22Ile	missense	Exon 1 of 4	ENSP00000357288.4	Q9Y2Q5-1
	LAMTOR2	ENST00000871951.1		c.65C>T	p.Thr22Ile	missense	Exon 1 of 5	ENSP00000542010.1
	LAMTOR2	ENST00000368302.3	TSL:3	c.65C>T	p.Thr22Ile	missense	Exon 1 of 4	ENSP00000357285.3	Q9Y2Q5-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000406 AC: 1 AN: 246308 AF XY: 0.00000746

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: 0.00000906

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459696 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726132

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 86106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5434

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111550

Other (OTH) AF: 0.0000166 AC: 1 AN: 60298

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.3
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.23
Sift	Uncertain	0.010	D
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.66
MutPred		0.55		Loss of disorder (P = 0.0484)
MVP		0.36
MPC		2.1
ClinPred		0.99	D
GERP RS		4.7
PromoterAI		-0.041	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.80
gMVP		0.89
Mutation Taster		=17/83	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: rs751699653; hg19: chr1-156024745;