rs55739947

Variant names:

• chr15-101010802-C-A
• rs55739947
• NM_024652.6:c.1246C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024652.6(LRRK1):​c.1246C>A​(p.Leu416Met) variant causes a missense change. The variant allele was found at a frequency of 0.0102 in 1,613,954 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L416L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0086 (11 hom., cov: 31)
  • Exomes 𝑓: 0.010 (101 hom.)
• Consequence: LRRK1 NM_024652.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.53
• Publications: 19 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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068701804).
• BP6: Variant 15-101010802-C-A is Benign according to our data. Variant chr15-101010802-C-A is described in ClinVar as Benign. ClinVar VariationId is 719736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00864 (1315/152260) while in subpopulation SAS AF = 0.0159 (77/4830). AF 95% confidence interval is 0.0131. There are 11 homozygotes in GnomAd4. There are 683 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK1	NM_024652.6	c.1246C>A	p.Leu416Met	missense_variant	Exon 9 of 34	ENST00000388948.8	NP_078928.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRK1	ENST00000388948.8	c.1246C>A	p.Leu416Met	missense_variant	Exon 9 of 34	5	NM_024652.6	ENSP00000373600.3
LRRK1	ENST00000525284.5	n.1246C>A		non_coding_transcript_exon_variant	Exon 8 of 33	1		ENSP00000433069.1
LRRK1	ENST00000531270.5	n.1246C>A		non_coding_transcript_exon_variant	Exon 8 of 32	1		ENSP00000431668.1

Frequencies

GnomAD3 genomes AF: 0.00861 AC: 1310 AN: 152140 Hom.: 10 Cov.: 31

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0129

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00596

Gnomad SAS AF: 0.0159

Gnomad FIN AF: 0.0161

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00970

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00934 AC: 2330 AN: 249426 AF XY: 0.0100

Gnomad AFR exome AF: 0.00239

Gnomad AMR exome AF: 0.00475

Gnomad ASJ exome AF: 0.0119

Gnomad EAS exome AF: 0.00507

Gnomad FIN exome AF: 0.0134

Gnomad NFE exome AF: 0.00940

Gnomad OTH exome AF: 0.0115

GnomAD4 exome AF: 0.0103 AC: 15109 AN: 1461694 Hom.: 101 Cov.: 34 AF XY: 0.0107 AC XY: 7753 AN XY: 727156

African (AFR) AF: 0.00266 AC: 89 AN: 33472

American (AMR) AF: 0.00568 AC: 254 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0116 AC: 302 AN: 26132

East Asian (EAS) AF: 0.00710 AC: 282 AN: 39700

South Asian (SAS) AF: 0.0154 AC: 1329 AN: 86222

European-Finnish (FIN) AF: 0.0130 AC: 696 AN: 53410

Middle Eastern (MID) AF: 0.0395 AC: 228 AN: 5768

European-Non Finnish (NFE) AF: 0.0100 AC: 11172 AN: 1111904

Other (OTH) AF: 0.0125 AC: 757 AN: 60386

GnomAD4 genome AF: 0.00864 AC: 1315 AN: 152260 Hom.: 11 Cov.: 31 AF XY: 0.00917 AC XY: 683 AN XY: 74456

African (AFR) AF: 0.00248 AC: 103 AN: 41540

American (AMR) AF: 0.0129 AC: 197 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3472

East Asian (EAS) AF: 0.00598 AC: 31 AN: 5186

South Asian (SAS) AF: 0.0159 AC: 77 AN: 4830

European-Finnish (FIN) AF: 0.0161 AC: 171 AN: 10608

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00970 AC: 660 AN: 68012

Other (OTH) AF: 0.0147 AC: 31 AN: 2116

Alfa AF: 0.0100 Hom.: 18

Bravo AF: 0.00794

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00134 AC: 5

ESP6500EA AF: 0.00949 AC: 78

ExAC AF: 0.00853 AC: 1031

Asia WGS AF: 0.0290 AC: 100 AN: 3478

EpiCase AF: 0.0112

EpiControl AF: 0.0107

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

LRRK1-related disorder Benign:1

Feb 23, 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
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.5
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.29
Sift	Uncertain	0.017	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.68
MVP		0.72
MPC		1.2
ClinPred		0.019	T
GERP RS		2.0
Varity_R		0.24
gMVP		0.54
Mutation Taster		=97/3	polymorphism

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: rs55739947; hg19: chr15-101551007; COSMIC: COSV99033967;