15-100924710-T-C

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.78T>C(p.Arg26=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,612,990 control chromosomes in the GnomAD database, including 65,240 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (10949 hom., cov: 32)
  • Exomes 𝑓: 0.26 (54291 hom.)
• Consequence: LRRK1 NM_024652.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.150

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 15-100924710-T-C is Benign according to our data. Variant chr15-100924710-T-C is described in ClinVar as [Benign]. Clinvar id is 1599963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK1	NM_024652.6	c.78T>C	p.Arg26=	synonymous_variant	2/34	ENST00000388948.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK1	ENST00000388948.8	c.78T>C	p.Arg26=	synonymous_variant	2/34	5	NM_024652.6	P1

Frequencies

GnomAD3 genomes AF: 0.339 AC: 51526 AN: 151890 Hom.: 10927 Cov.: 32

Gnomad AFR AF: 0.601

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.314

GnomAD3 exomes AF: 0.255 AC: 63867 AN: 250810 Hom.: 9858 AF XY: 0.255 AC XY: 34554 AN XY: 135598

Gnomad AFR exome AF: 0.619

Gnomad AMR exome AF: 0.129

Gnomad ASJ exome AF: 0.304

Gnomad EAS exome AF: 0.119

Gnomad SAS exome AF: 0.291

Gnomad FIN exome AF: 0.210

Gnomad NFE exome AF: 0.258

Gnomad OTH exome AF: 0.244

GnomAD4 exome AF: 0.264 AC: 385404 AN: 1460982 Hom.: 54291 Cov.: 32 AF XY: 0.264 AC XY: 191702 AN XY: 726822

Gnomad4 AFR exome AF: 0.621

Gnomad4 AMR exome AF: 0.140

Gnomad4 ASJ exome AF: 0.301

Gnomad4 EAS exome AF: 0.126

Gnomad4 SAS exome AF: 0.291

Gnomad4 FIN exome AF: 0.214

Gnomad4 NFE exome AF: 0.261

Gnomad4 OTH exome AF: 0.281

GnomAD4 genome AF: 0.339 AC: 51603 AN: 152008 Hom.: 10949 Cov.: 32 AF XY: 0.331 AC XY: 24569 AN XY: 74298

Gnomad4 AFR AF: 0.601

Gnomad4 AMR AF: 0.223

Gnomad4 ASJ AF: 0.298

Gnomad4 EAS AF: 0.126

Gnomad4 SAS AF: 0.298

Gnomad4 FIN AF: 0.193

Gnomad4 NFE AF: 0.254

Gnomad4 OTH AF: 0.318

Alfa AF: 0.287 Hom.: 6579

Bravo AF: 0.350

Asia WGS AF: 0.256 AC: 893 AN: 3478

EpiCase AF: 0.259

EpiControl AF: 0.259

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	-0.85
Cadd	Benign	4.6
Dann	Benign	0.62

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: rs11630691; hg19: chr15-101464915; COSMIC: COSV52617349;