rs2924835

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024652.6(LRRK1):c.5813G>A(p.Gly1938Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 1,612,632 control chromosomes in the GnomAD database, including 76,059 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 5794 hom., cov: 33)

Exomes 𝑓: 0.31 ( 70265 hom. )

Consequence

LRRK1
NM_024652.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.10

Variant links:

Genes affected

LRRK1 (HGNC:18608): (leucine rich repeat kinase 1) This gene encodes a multi-domain protein that is a leucine-rich repeat kinase and a GDP/GTP binding protein. The encoded protein is thought to play a role in the regulation of bone mass. Mice lacking a similar gene showed severe osteopetrosis, increased bone mineralization and decreased bone resorption. [provided by RefSeq, Jan 2017]

LRRK1 links:

ENSG00000259755 (HGNC:58299):

ENSG00000259755 links:

LOC105371026 (HGNC:):

LOC105371026 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0050085187).

BP6

Variant 15-101066684-G-A is Benign according to our data. Variant chr15-101066684-G-A is described in ClinVar as [Benign]. Clinvar id is 1248289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.325 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK1	NM_024652.6 link	c.5813G>A	p.Gly1938Asp	missense_variant	Exon 33 of 34	ENST00000388948.8	NP_078928.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRK1	ENST00000388948.8 link	c.5813G>A	p.Gly1938Asp	missense_variant	Exon 33 of 34	5	NM_024652.6	ENSP00000373600.3		Q38SD2-1

Frequencies

GnomAD3 genomes

AF:

0.260

AC:

39563

AN:

151920

Hom.:

5793

Cov.:

show subpopulations

Gnomad AFR

AF:

0.108

Gnomad AMI

AF:

0.267

Gnomad AMR

AF:

0.318

Gnomad ASJ

AF:

0.291

Gnomad EAS

AF:

0.339

Gnomad SAS

AF:

0.331

Gnomad FIN

AF:

0.345

Gnomad MID

AF:

0.342

Gnomad NFE

AF:

0.313

Gnomad OTH

AF:

0.283

GnomAD3 exomes

AF:

0.309

AC:

77048

AN:

249370

Hom.:

12289

AF XY:

0.312

AC XY:

42196

AN XY:

135278

show subpopulations

Gnomad AFR exome

AF:

0.104

Gnomad AMR exome

AF:

0.334

Gnomad ASJ exome

AF:

0.279

Gnomad EAS exome

AF:

0.360

Gnomad SAS exome

AF:

0.317

Gnomad FIN exome

AF:

0.342

Gnomad NFE exome

AF:

0.315

Gnomad OTH exome

AF:

0.318

GnomAD4 exome

AF:

0.308

AC:

449344

AN:

1460594

Hom.:

70265

Cov.:

AF XY:

0.309

AC XY:

224396

AN XY:

726688

show subpopulations

Gnomad4 AFR exome

AF:

0.103

Gnomad4 AMR exome

AF:

0.327

Gnomad4 ASJ exome

AF:

0.286

Gnomad4 EAS exome

AF:

0.356

Gnomad4 SAS exome

AF:

0.320

Gnomad4 FIN exome

AF:

0.337

Gnomad4 NFE exome

AF:

0.310

Gnomad4 OTH exome

AF:

0.296

GnomAD4 genome

AF:

0.260

AC:

39571

AN:

152038

Hom.:

5794

Cov.:

AF XY:

0.266

AC XY:

19782

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.108

Gnomad4 AMR

AF:

0.318

Gnomad4 ASJ

AF:

0.291

Gnomad4 EAS

AF:

0.339

Gnomad4 SAS

AF:

0.331

Gnomad4 FIN

AF:

0.345

Gnomad4 NFE

AF:

0.313

Gnomad4 OTH

AF:

0.281

Alfa

AF:

0.301

Hom.:

7538

Bravo

AF:

0.254

TwinsUK

AF:

0.307

AC:

1140

ALSPAC

AF:

0.313

AC:

1207

ESP6500AA

AF:

0.101

AC:

418

ESP6500EA

AF:

0.302

AC:

2545

ExAC

AF:

0.304

AC:

36809

Asia WGS

AF:

0.239

AC:

831

AN:

3478

EpiCase

AF:

0.313

EpiControl

AF:

0.312

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

LRRK1-related disorder

Benign:1

Oct 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.019

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0050

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.3

REVEL

Benign

0.20

Sift

Benign

0.049

Sift4G

Benign

0.44

Polyphen

0.016

Vest4

0.11

MPC

0.53

ClinPred

0.013

GERP RS

5.5

Varity_R

0.14

gMVP

0.43

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over