rs17161161

chr15-101066089-C-T

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.5652C>T(p.Pro1884=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00882 in 1,614,102 control chromosomes in the GnomAD database, including 922 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (498 hom., cov: 33)
  • Exomes 𝑓: 0.0051 (424 hom.)
• Consequence: LRRK1 NM_024652.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.477

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=-0.8).
• BP6: Variant 15-101066089-C-T is Benign according to our data. Variant chr15-101066089-C-T is described in ClinVar as [Benign]. Clinvar id is 1548827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.477 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.151 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK1	NM_024652.6	c.5652C>T	p.Pro1884=	synonymous_variant	32/34	ENST00000388948.8
LOC105371026	XR_001751726.2	n.1051-15310G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK1	ENST00000388948.8	c.5652C>T	p.Pro1884=	synonymous_variant	32/34	5	NM_024652.6	P1
	ENST00000559857.1	n.369-425G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0447 AC: 6799 AN: 152170 Hom.: 494 Cov.: 33

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0153

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.0345

GnomAD3 exomes AF: 0.0119 AC: 2944 AN: 247866 Hom.: 207 AF XY: 0.00900 AC XY: 1212 AN XY: 134608

Gnomad AFR exome AF: 0.157

Gnomad AMR exome AF: 0.00672

Gnomad ASJ exome AF: 0.0155

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000716

Gnomad OTH exome AF: 0.00611

GnomAD4 exome AF: 0.00507 AC: 7408 AN: 1461814 Hom.: 424 Cov.: 32 AF XY: 0.00445 AC XY: 3239 AN XY: 727218

Gnomad4 AFR exome AF: 0.160

Gnomad4 AMR exome AF: 0.00762

Gnomad4 ASJ exome AF: 0.0158

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000499

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000487

Gnomad4 OTH exome AF: 0.0111

GnomAD4 genome AF: 0.0448 AC: 6823 AN: 152288 Hom.: 498 Cov.: 33 AF XY: 0.0435 AC XY: 3243 AN XY: 74468

Gnomad4 AFR AF: 0.154

Gnomad4 AMR AF: 0.0153

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.0341

Alfa AF: 0.0235 Hom.: 135

Bravo AF: 0.0508

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00124

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

Mar 25, 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 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	9.4
Dann	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17161161; hg19: chr15-101606294;