Genetic Variant LAMP3:p.Pro218Leu (chr3-183153788-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_014398.4(LAMP3):c.653C>T(p.Pro218Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000056 in 1,429,072 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: 0.0000056 ( 0 hom. )

Consequence

LAMP3
NM_014398.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.48

Publications

0 publications found

Variant links:

Genes affected

LAMP3 (HGNC:14582): (lysosomal associated membrane protein 3) Dendritic cells (DCs) are the most potent antigen-presenting cells. Immature DCs efficiently capture antigens and differentiate into interdigitating dendritic cells (IDCs) in lymphoid tissues that induce primary T-cell responses (summary by de Saint-Vis et al., 1998 [PubMed 9768752]).[supplied by OMIM, Dec 2010]

LAMP3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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
LAMP3	NM_014398.4 link	c.653C>T	p.Pro218Leu	missense_variant	Exon 2 of 6	ENST00000265598.8	NP_055213.2	Q9UQV4
LAMP3	XM_005247360.6 link	c.653C>T	p.Pro218Leu	missense_variant	Exon 3 of 7		XP_005247417.1
LAMP3	XM_047447967.1 link	c.653C>T	p.Pro218Leu	missense_variant	Exon 2 of 6		XP_047303923.1
LAMP3	XM_011512688.3 link	c.653C>T	p.Pro218Leu	missense_variant	Exon 2 of 6		XP_011510990.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LAMP3	ENST00000265598.8 link	c.653C>T	p.Pro218Leu	missense_variant	Exon 2 of 6	1	NM_014398.4	ENSP00000265598.3	Q9UQV4
LAMP3	ENST00000466939.1 link	c.581C>T	p.Pro194Leu	missense_variant	Exon 2 of 6	2		ENSP00000418912.1	E7ETP9
LAMP3	ENST00000476015.1 link	c.*113C>T		downstream_gene_variant		4		ENSP00000419059.1	C9JYP5
LAMP3	ENST00000470251.1 link	c.*152C>T		downstream_gene_variant		2		ENSP00000420589.1	C9JDI8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000560

AC:

AN:

1429072

Hom.:

Cov.:

AF XY:

0.00000566

AC XY:

AN XY:

707126

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32730

American (AMR)

AF:

0.00

AC:

AN:

41148

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23572

East Asian (EAS)

AF:

0.00

AC:

AN:

39480

South Asian (SAS)

AF:

0.00

AC:

AN:

79356

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51990

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5610

European-Non Finnish (NFE)

AF:

0.00000730

AC:

AN:

1096172

Other (OTH)

AF:

0.00

AC:

AN:

59014

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.419

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 19, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.653C>T (p.P218L) alteration is located in exon 2 (coding exon 2) of the LAMP3 gene. This alteration results from a C to T substitution at nucleotide position 653, causing the proline (P) at amino acid position 218 to be replaced by a leucine (L). 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

0.12

BayesDel_addAF

Uncertain

0.023

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.86

D;D

M_CAP

Benign

0.024

MetaRNN

Uncertain

0.56

D;D

MetaSVM

Benign

-0.61

MutationAssessor

Pathogenic

3.2

M;.

PhyloP100

5.5

PrimateAI

Benign

0.36

PROVEAN

Pathogenic

-8.4

D;D

REVEL

Uncertain

0.30

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

D;.

Vest4

0.36

MutPred

0.64

Loss of disorder (P = 0.0347);.;

MVP

0.47

MPC

0.41

ClinPred

0.99

GERP RS

5.8

Varity_R

0.59

gMVP

0.40

Mutation Taster

=85/15

polymorphism

(source)

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

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3-183153788-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over