rs55739947

Positions:

chr15-101010802-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024652.6(LRRK1):c.1246C>A(p.Leu416Met) variant causes a missense change. The variant allele was found at a frequency of 0.0102 in 1,613,954 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0086 ( 11 hom., cov: 31)

Exomes 𝑓: 0.010 ( 101 hom. )

Consequence

LRRK1
NM_024652.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.53

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0068701804).

BP6

Variant 15-101010802-C-A is Benign according to our data. Variant chr15-101010802-C-A is described in ClinVar as [Benign]. Clinvar id is 719736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00864 (1315/152260) while in subpopulation SAS AF= 0.0159 (77/4830). AF 95% confidence interval is 0.0131. There are 11 homozygotes in gnomad4. There are 683 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRK1	NM_024652.6 linkuse as main transcript	c.1246C>A	p.Leu416Met	missense_variant	9/34	ENST00000388948.8	NP_078928.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRK1	ENST00000388948.8 linkuse as main transcript	c.1246C>A	p.Leu416Met	missense_variant	9/34	5	NM_024652.6	ENSP00000373600	P1	Q38SD2-1
LRRK1	ENST00000525284.5 linkuse as main transcript	c.1246C>A	p.Leu416Met	missense_variant, NMD_transcript_variant	8/33	1		ENSP00000433069
LRRK1	ENST00000531270.5 linkuse as main transcript	c.1246C>A	p.Leu416Met	missense_variant, NMD_transcript_variant	8/32	1		ENSP00000431668

Frequencies

GnomAD3 genomes

AF:

0.00861

AC:

1310

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00249

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0129

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.00596

Gnomad SAS

AF:

0.0159

Gnomad FIN

AF:

0.0161

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.00970

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.00934

AC:

2330

AN:

249426

Hom.:

AF XY:

0.0100

AC XY:

1358

AN XY:

135336

show subpopulations

Gnomad AFR exome

AF:

0.00239

Gnomad AMR exome

AF:

0.00475

Gnomad ASJ exome

AF:

0.0119

Gnomad EAS exome

AF:

0.00507

Gnomad SAS exome

AF:

0.0162

Gnomad FIN exome

AF:

0.0134

Gnomad NFE exome

AF:

0.00940

Gnomad OTH exome

AF:

0.0115

GnomAD4 exome

AF:

0.0103

AC:

15109

AN:

1461694

Hom.:

101

Cov.:

AF XY:

0.0107

AC XY:

7753

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.00266

Gnomad4 AMR exome

AF:

0.00568

Gnomad4 ASJ exome

AF:

0.0116

Gnomad4 EAS exome

AF:

0.00710

Gnomad4 SAS exome

AF:

0.0154

Gnomad4 FIN exome

AF:

0.0130

Gnomad4 NFE exome

AF:

0.0100

Gnomad4 OTH exome

AF:

0.0125

GnomAD4 genome

AF:

0.00864

AC:

1315

AN:

152260

Hom.:

Cov.:

AF XY:

0.00917

AC XY:

683

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00248

Gnomad4 AMR

AF:

0.0129

Gnomad4 ASJ

AF:

0.0104

Gnomad4 EAS

AF:

0.00598

Gnomad4 SAS

AF:

0.0159

Gnomad4 FIN

AF:

0.0161

Gnomad4 NFE

AF:

0.00970

Gnomad4 OTH

AF:

0.0147

Alfa

AF:

0.0104

Hom.:

Bravo

AF:

0.00794

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00134

AC:

ESP6500EA

AF:

0.00949

AC:

ExAC

AF:

0.00853

AC:

1031

Asia WGS

AF:

0.0290

AC:

100

AN:

3478

EpiCase

AF:

0.0112

EpiControl

AF:

0.0107

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

LRRK1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 23, 2019

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

0.21

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0069

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.29

Sift

Uncertain

0.017

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.68

MVP

0.72

MPC

1.2

ClinPred

0.019

GERP RS

2.0

Varity_R

0.24

gMVP

0.54

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