rs35985016

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024652.6(LRRK1):c.607A>G(p.Lys203Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 1,597,388 control chromosomes in the GnomAD database, including 168 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 9 hom., cov: 33)

Exomes 𝑓: 0.0033 ( 159 hom. )

Consequence

LRRK1
NM_024652.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.41

Publications

9 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044516325).

BP6

Variant 15-100988807-A-G is Benign according to our data. Variant chr15-100988807-A-G is described in ClinVar as Benign. ClinVar VariationId is 1537753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0726 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK1	NM_024652.6 link	c.607A>G	p.Lys203Glu	missense_variant	Exon 5 of 34	ENST00000388948.8	NP_078928.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LRRK1	ENST00000388948.8 link	c.607A>G	p.Lys203Glu	missense_variant	Exon 5 of 34	5	NM_024652.6	ENSP00000373600.3	Q38SD2-1
LRRK1	ENST00000532029.6 link	c.607A>G	p.Lys203Glu	missense_variant	Exon 5 of 6	1		ENSP00000433268.2	Q38SD2-2
LRRK1	ENST00000525284.5 link	n.607A>G		non_coding_transcript_exon_variant	Exon 4 of 33	1		ENSP00000433069.1	E9PMK9
LRRK1	ENST00000531270.5 link	n.607A>G		non_coding_transcript_exon_variant	Exon 4 of 32	1		ENSP00000431668.1	E9PK39

Frequencies

GnomAD3 genomes

AF:

0.00282

AC:

430

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0420

Gnomad SAS

AF:

0.00828

Gnomad FIN

AF:

0.0105

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.00240

GnomAD2 exomes

AF:

0.00487

AC:

1171

AN:

240406

AF XY:

0.00485

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.000119

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0351

Gnomad FIN exome

AF:

0.00909

Gnomad NFE exome

AF:

0.00132

Gnomad OTH exome

AF:

0.00550

GnomAD4 exome

AF:

0.00326

AC:

4718

AN:

1445054

Hom.:

159

Cov.:

AF XY:

0.00342

AC XY:

2447

AN XY:

715986

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33196

American (AMR)

AF:

0.000114

AC:

AN:

43918

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25314

East Asian (EAS)

AF:

0.0749

AC:

2951

AN:

39424

South Asian (SAS)

AF:

0.00655

AC:

554

AN:

84540

European-Finnish (FIN)

AF:

0.00921

AC:

488

AN:

52968

Middle Eastern (MID)

AF:

0.00403

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.000457

AC:

503

AN:

1100428

Other (OTH)

AF:

0.00326

AC:

194

AN:

59562

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

241

482

723

964

1205

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00281

AC:

428

AN:

152334

Hom.:

Cov.:

AF XY:

0.00368

AC XY:

274

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.0000721

AC:

AN:

41582

American (AMR)

AF:

0.000392

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0419

AC:

217

AN:

5178

South Asian (SAS)

AF:

0.00808

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0105

AC:

111

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000691

AC:

AN:

68036

Other (OTH)

AF:

0.00237

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00278

Hom.:

Bravo

AF:

0.00206

ESP6500AA

AF:

0.000728

AC:

ESP6500EA

AF:

0.00119

AC:

ExAC

AF:

0.00507

AC:

613

Asia WGS

AF:

0.0170

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 05, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

LRRK1-related disorder

Benign:1

Sep 26, 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

0.23

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.014

T;.

Eigen

Benign

-0.086

Eigen_PC

Benign

0.090

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.82

T;T

MetaRNN

Benign

0.0045

T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.55

N;N

PhyloP100

3.4

PrimateAI

Uncertain

0.59

PROVEAN

Benign

0.24

N;N

REVEL

Benign

0.042

Sift

Benign

0.043

D;T

Sift4G

Benign

0.068

T;D

Polyphen

0.011

B;B

Vest4

0.43

MVP

0.83

MPC

0.58

ClinPred

0.020

GERP RS

5.2

Varity_R

0.13

gMVP

0.58

Mutation Taster

=97/3

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over