Genetic Variant LAMP1:p.Leu18Pro (chr13-113297487-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_005561.4(LAMP1):c.53T>C(p.Leu18Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000908 in 1,101,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 9.1e-7 ( 0 hom. )

Consequence

LAMP1
NM_005561.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.31

Publications

0 publications found

Variant links:

Genes affected

LAMP1 (HGNC:6499): (lysosomal associated membrane protein 1) The protein encoded by this gene is a member of a family of membrane glycoproteins. This glycoprotein provides selectins with carbohydrate ligands. It may also play a role in tumor cell metastasis. [provided by RefSeq, Jul 2008]

LAMP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.838

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMP1	NM_005561.4 link	c.53T>C	p.Leu18Pro	missense_variant	Exon 1 of 9	ENST00000332556.5	NP_005552.3	P11279-1A0A024RDY3
LAMP1	XM_047430302.1 link	c.-256T>C		upstream_gene_variant			XP_047286258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMP1	ENST00000332556.5 link	c.53T>C	p.Leu18Pro	missense_variant	Exon 1 of 9	1	NM_005561.4	ENSP00000333298.4		P11279-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.08e-7

AC:

AN:

1101200

Hom.:

Cov.:

AF XY:

0.00000189

AC XY:

AN XY:

527814

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

22972

American (AMR)

AF:

0.00

AC:

AN:

8580

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14392

East Asian (EAS)

AF:

0.00

AC:

AN:

26864

South Asian (SAS)

AF:

0.00

AC:

AN:

25788

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21862

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2962

European-Non Finnish (NFE)

AF:

0.00000107

AC:

AN:

933504

Other (OTH)

AF:

0.00

AC:

AN:

44276

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 13, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.53T>C (p.L18P) alteration is located in exon 1 (coding exon 1) of the LAMP1 gene. This alteration results from a T to C substitution at nucleotide position 53, causing the leucine (L) at amino acid position 18 to be replaced by a proline (P). 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

0.097

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Benign

0.083

Eigen_PC

Benign

0.035

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.24

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.84

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.7

PhyloP100

2.3

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.6

REVEL

Benign

0.27

Sift

Benign

0.18

Sift4G

Uncertain

0.017

Polyphen

0.99

Vest4

0.66

MutPred

0.65

Loss of stability (P = 0.0031);

MVP

0.47

MPC

0.61

ClinPred

0.31

GERP RS

2.0

PromoterAI

-0.018

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.32

gMVP

0.45

Mutation Taster

=83/17

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over