rs41372244

chr15-101055052-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024652.6(LRRK1):c.4161G>A(p.Leu1387=) 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:2
• Conservation: PhyloP100: 0.699

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
LRRK1	NM_024652.6	c.4161G>A	p.Leu1387=	synonymous_variant	27/34	ENST00000388948.8
LOC105371026	XR_001751726.2	n.1051-4273C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK1	ENST00000388948.8	c.4161G>A	p.Leu1387=	synonymous_variant	27/34	5	NM_024652.6	P1
	ENST00000559857.1	n.673-4273C>T		intron_variant, non_coding_transcript_variant		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

GnomAD3 exomes AF: 0.137 AC: 34202 AN: 249418 Hom.: 3898 AF XY: 0.128 AC XY: 17330 AN XY: 135338

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 SAS exome AF: 0.0969

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

Gnomad4 AFR exome AF: 0.0264

Gnomad4 AMR exome AF: 0.284

Gnomad4 ASJ exome AF: 0.0931

Gnomad4 EAS exome AF: 0.351

Gnomad4 SAS exome AF: 0.0959

Gnomad4 FIN exome AF: 0.148

Gnomad4 NFE exome AF: 0.0742

Gnomad4 OTH exome AF: 0.101

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

Gnomad4 AFR AF: 0.0294

Gnomad4 AMR AF: 0.193

Gnomad4 ASJ AF: 0.100

Gnomad4 EAS AF: 0.373

Gnomad4 SAS AF: 0.109

Gnomad4 FIN AF: 0.150

Gnomad4 NFE AF: 0.0788

Gnomad4 OTH AF: 0.102

Alfa AF: 0.0777 Hom.: 294

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

LRRK1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	5.5
Dann	Benign	0.77

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

Other links and lift over

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