Genetic Variant NM_005561.4:c.53T>C (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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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