NM_002294.3:c.1117G>T

Variant names:

• chrX-120431439-C-A
• rs727503117
• NM_002294.3:c.1117G>T

Variant summary

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

The NM_002294.3(LAMP2):​c.1117G>T​(p.Asp373Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,096,328 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D373N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 1 hem.)
• Consequence: LAMP2 NM_002294.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.32
• Publications: 3 publications found

Genes affected

LAMP2 (HGNC:6501): (lysosomal associated membrane protein 2) The protein encoded by this gene is a member of a family of membrane glycoproteins. This glycoprotein provides selectins with carbohydrate ligands. It may play a role in tumor cell metastasis. It may also function in the protection, maintenance, and adhesion of the lysosome. Alternative splicing of this gene results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jul 2008]

LAMP2 Gene-Disease associations (from GenCC):

• Danon disease

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 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
LAMP2	NM_002294.3	c.1117G>T	p.Asp373Tyr	missense_variant	Exon 9 of 9	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.1094-2813G>T		intron_variant	Intron 8 of 8		NP_001116078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9	c.1117G>T	p.Asp373Tyr	missense_variant	Exon 9 of 9	1	NM_002294.3	ENSP00000200639.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000552 AC: 1 AN: 181117 AF XY: 0.00

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: 0.0000126

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 3 AN: 1096328 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 1 AN XY: 361916

African (AFR) AF: 0.00 AC: 0 AN: 26354

American (AMR) AF: 0.00 AC: 0 AN: 35186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19344

East Asian (EAS) AF: 0.00 AC: 0 AN: 30185

South Asian (SAS) AF: 0.00 AC: 0 AN: 54076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40521

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4123

European-Non Finnish (NFE) AF: 0.00000357 AC: 3 AN: 840522

Other (OTH) AF: 0.00 AC: 0 AN: 46017

GnomAD4 genome Cov.: 23

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Oct 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D373Y variant (also known as c.1117G>T), located in coding exon 9 of the LAMP2 gene, results from a G to T substitution at nucleotide position 1117. The aspartic acid at codon 373 is replaced by tyrosine, an amino acid with highly dissimilar properties. Based on data from gnomAD, the T allele has an overall frequency of <0.01% (1/181117) total alleles studied, with 0 hemizygote(s) observed. The highest observed frequency was <0.01% (1/79656) of European (non-Finnish) alleles. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
CardioboostCm	Benign	0.0061
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		4.3
PROVEAN	Pathogenic	-5.5	D
REVEL	Benign	0.28
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.45
MutPred		0.55		Gain of phosphorylation at D373 (P = 0.0403);
MVP		0.52
ClinPred		0.71	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
Mutation Taster		=45/55	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: rs727503117; hg19: chrX-119565294;