rs35985016

Positions:

• chr15-100988807-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024652.6(LRRK1):​c.607A>G​(p.Lys203Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 1,597,388 control chromosomes in the GnomAD database, including 168 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (159 hom.)
• Consequence: LRRK1 NM_024652.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.41

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044516325).
• BP6: Variant 15-100988807-A-G is Benign according to our data. Variant chr15-100988807-A-G is described in ClinVar as [Benign]. Clinvar id is 1537753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0726 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRK1	NM_024652.6	c.607A>G	p.Lys203Glu	missense_variant	5/34	ENST00000388948.8	NP_078928.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRK1	ENST00000388948.8	c.607A>G	p.Lys203Glu	missense_variant	5/34	5	NM_024652.6	ENSP00000373600	P1
LRRK1	ENST00000532029.6	c.607A>G	p.Lys203Glu	missense_variant	5/6	1		ENSP00000433268
LRRK1	ENST00000525284.5	c.607A>G	p.Lys203Glu	missense_variant, NMD_transcript_variant	4/33	1		ENSP00000433069
LRRK1	ENST00000531270.5	c.607A>G	p.Lys203Glu	missense_variant, NMD_transcript_variant	4/32	1		ENSP00000431668

Frequencies

GnomAD3 genomes AF: 0.00282 AC: 430 AN: 152216 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0420

Gnomad SAS AF: 0.00828

Gnomad FIN AF: 0.0105

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00487 AC: 1171 AN: 240406 Hom.: 22 AF XY: 0.00485 AC XY: 630 AN XY: 129946

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.000119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0351

Gnomad SAS exome AF: 0.00591

Gnomad FIN exome AF: 0.00909

Gnomad NFE exome AF: 0.00132

Gnomad OTH exome AF: 0.00550

GnomAD4 exome AF: 0.00326 AC: 4718 AN: 1445054 Hom.: 159 Cov.: 31 AF XY: 0.00342 AC XY: 2447 AN XY: 715986

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0749

Gnomad4 SAS exome AF: 0.00655

Gnomad4 FIN exome AF: 0.00921

Gnomad4 NFE exome AF: 0.000457

Gnomad4 OTH exome AF: 0.00326

GnomAD4 genome AF: 0.00281 AC: 428 AN: 152334 Hom.: 9 Cov.: 33 AF XY: 0.00368 AC XY: 274 AN XY: 74496

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0419

Gnomad4 SAS AF: 0.00808

Gnomad4 FIN AF: 0.0105

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00251 Hom.: 10

Bravo AF: 0.00206

ESP6500AA AF: 0.000728 AC: 3

ESP6500EA AF: 0.00119 AC: 10

ExAC AF: 0.00507 AC: 613

Asia WGS AF: 0.0170 AC: 60 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 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

Sep 26, 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	0.23
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.014	T;.
Eigen	Benign	-0.086
Eigen_PC	Benign	0.090
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T;T
MetaRNN	Benign	0.0045	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.55	N;N
MutationTaster	Benign	0.82	D;D;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.24	N;N
REVEL	Benign	0.042
Sift	Benign	0.043	D;T
Sift4G	Benign	0.068	T;D
Polyphen		0.011	B;B
Vest4		0.43
MVP		0.83
MPC		0.58
ClinPred		0.020	T
GERP RS		5.2
Varity_R		0.13
gMVP		0.58

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: rs35985016; hg19: chr15-101529012; COSMIC: COSV52619207;