Genetic Variant LAMP1:p.Ala2Glu (chr13-113297439-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005561.4(LAMP1):c.5C>A(p.Ala2Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000224 in 892,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

LAMP1
NM_005561.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.64

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28677523).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMP1	NM_005561.4 link	c.5C>A	p.Ala2Glu	missense_variant	Exon 1 of 9	ENST00000332556.5	NP_005552.3	P11279-1A0A024RDY3
LAMP1	XM_047430302.1 link	c.-304C>A		upstream_gene_variant			XP_047286258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMP1	ENST00000332556.5 link	c.5C>A	p.Ala2Glu	missense_variant	Exon 1 of 9	1	NM_005561.4	ENSP00000333298.4		P11279-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000224

AC:

AN:

892878

Hom.:

Cov.:

AF XY:

0.00000229

AC XY:

AN XY:

435902

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:

18656

American (AMR)

AF:

0.00

AC:

AN:

8682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12992

East Asian (EAS)

AF:

0.00

AC:

AN:

25270

South Asian (SAS)

AF:

0.00

AC:

AN:

22692

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21508

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2490

European-Non Finnish (NFE)

AF:

0.00000269

AC:

AN:

743500

Other (OTH)

AF:

0.00

AC:

AN:

37088

⚠️ 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: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.28

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.30

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.40

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

PhyloP100

1.6

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.5

REVEL

Benign

0.064

Sift

Benign

0.11

Sift4G

Benign

0.093

Polyphen

0.12

Vest4

0.25

MutPred

0.18

Gain of solvent accessibility (P = 0.0456);

MVP

0.17

MPC

0.35

ClinPred

0.48

GERP RS

1.2

PromoterAI

-0.21

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.64

Mutation Taster

=92/8

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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chr13-113297439-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over