rs41372244

Variant names:

• chr15-101055052-G-A
• rs41372244
• NM_024652.6:c.4161G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024652.6(LRRK1):​c.4161G>A​(p.Leu1387Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0926 in 1,613,920 control chromosomes in the GnomAD database, including 10,370 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (1136 hom., cov: 33)
  • Exomes 𝑓: 0.093 (9234 hom.)
• Consequence: LRRK1 NM_024652.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.699
• Publications: 14 publications found

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]

ENSG00000259755 (HGNC:58299):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 15-101055052-G-A is Benign according to our data. Variant chr15-101055052-G-A is described in ClinVar as Benign. ClinVar VariationId is 1589922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.699 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK1	NM_024652.6	c.4161G>A	p.Leu1387Leu	synonymous_variant	Exon 27 of 34	ENST00000388948.8	NP_078928.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRK1	ENST00000388948.8	c.4161G>A	p.Leu1387Leu	synonymous_variant	Exon 27 of 34	5	NM_024652.6	ENSP00000373600.3

Frequencies

GnomAD3 genomes AF: 0.0935 AC: 14219 AN: 152106 Hom.: 1140 Cov.: 33

Gnomad AFR AF: 0.0295

Gnomad AMI AF: 0.0637

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.100

Gnomad EAS AF: 0.374

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0788

Gnomad OTH AF: 0.102

GnomAD2 exomes AF: 0.137 AC: 34202 AN: 249418 AF XY: 0.128

Gnomad AFR exome AF: 0.0280

Gnomad AMR exome AF: 0.295

Gnomad ASJ exome AF: 0.0922

Gnomad EAS exome AF: 0.380

Gnomad FIN exome AF: 0.151

Gnomad NFE exome AF: 0.0785

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.0925 AC: 135218 AN: 1461696 Hom.: 9234 Cov.: 32 AF XY: 0.0919 AC XY: 66815 AN XY: 727150

African (AFR) AF: 0.0264 AC: 884 AN: 33480

American (AMR) AF: 0.284 AC: 12679 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0931 AC: 2434 AN: 26134

East Asian (EAS) AF: 0.351 AC: 13915 AN: 39674

South Asian (SAS) AF: 0.0959 AC: 8272 AN: 86238

European-Finnish (FIN) AF: 0.148 AC: 7895 AN: 53410

Middle Eastern (MID) AF: 0.0976 AC: 563 AN: 5768

European-Non Finnish (NFE) AF: 0.0742 AC: 82480 AN: 1111922

Other (OTH) AF: 0.101 AC: 6096 AN: 60394

GnomAD4 genome AF: 0.0934 AC: 14214 AN: 152224 Hom.: 1136 Cov.: 33 AF XY: 0.101 AC XY: 7486 AN XY: 74422

African (AFR) AF: 0.0294 AC: 1220 AN: 41562

American (AMR) AF: 0.193 AC: 2950 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 347 AN: 3470

East Asian (EAS) AF: 0.373 AC: 1926 AN: 5166

South Asian (SAS) AF: 0.109 AC: 524 AN: 4824

European-Finnish (FIN) AF: 0.150 AC: 1593 AN: 10594

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0788 AC: 5357 AN: 67998

Other (OTH) AF: 0.102 AC: 215 AN: 2112

Alfa AF: 0.0830 Hom.: 820

Bravo AF: 0.0978

Asia WGS AF: 0.224 AC: 780 AN: 3478

EpiCase AF: 0.0743

EpiControl AF: 0.0767

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 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

Oct 21, 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
BayesDel_noAF	Benign	-0.49
CADD	Benign	5.5
DANN	Benign	0.77
PhyloP100		0.70
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs41372244; hg19: chr15-101595257; COSMIC: COSV52600622; COSMIC: COSV52600622;