rs3764739

Variant names:

• chr15-101066056-C-T
• rs3764739
• NM_024652.6:c.5619C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024652.6(LRRK1):​c.5619C>T​(p.Thr1873Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0842 in 1,614,034 control chromosomes in the GnomAD database, including 8,757 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (955 hom., cov: 33)
  • Exomes 𝑓: 0.084 (7802 hom.)
• Consequence: LRRK1 NM_024652.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -6.26
• Publications: 15 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]

ENSG00000259755 (HGNC:58299):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 15-101066056-C-T is Benign according to our data. Variant chr15-101066056-C-T is described in ClinVar as Benign. ClinVar VariationId is 1574345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.26 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.336 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024652.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK1	NM_024652.6	MANE Select	c.5619C>T	p.Thr1873Thr	synonymous	Exon 32 of 34	NP_078928.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK1	ENST00000388948.8	TSL:5 MANE Select	c.5619C>T	p.Thr1873Thr	synonymous	Exon 32 of 34	ENSP00000373600.3
	LRRK1	ENST00000525284.5	TSL:1	n.*3745C>T		non_coding_transcript_exon	Exon 31 of 33	ENSP00000433069.1
	LRRK1	ENST00000526457.3	TSL:1	n.1647C>T		non_coding_transcript_exon	Exon 7 of 10	ENSP00000436672.2

Frequencies

GnomAD3 genomes AF: 0.0850 AC: 12933 AN: 152088 Hom.: 957 Cov.: 33

Gnomad AFR AF: 0.0250

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.0798

Gnomad EAS AF: 0.350

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0698

Gnomad OTH AF: 0.0943

GnomAD2 exomes AF: 0.126 AC: 31297 AN: 248732 AF XY: 0.119

Gnomad AFR exome AF: 0.0223

Gnomad AMR exome AF: 0.258

Gnomad ASJ exome AF: 0.0758

Gnomad EAS exome AF: 0.348

Gnomad FIN exome AF: 0.145

Gnomad NFE exome AF: 0.0704

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.0841 AC: 123007 AN: 1461826 Hom.: 7802 Cov.: 32 AF XY: 0.0842 AC XY: 61220 AN XY: 727218

African (AFR) AF: 0.0218 AC: 730 AN: 33480

American (AMR) AF: 0.251 AC: 11204 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0798 AC: 2085 AN: 26136

East Asian (EAS) AF: 0.324 AC: 12874 AN: 39700

South Asian (SAS) AF: 0.107 AC: 9242 AN: 86254

European-Finnish (FIN) AF: 0.141 AC: 7515 AN: 53364

Middle Eastern (MID) AF: 0.0960 AC: 554 AN: 5768

European-Non Finnish (NFE) AF: 0.0657 AC: 73082 AN: 1112006

Other (OTH) AF: 0.0947 AC: 5721 AN: 60394

GnomAD4 genome AF: 0.0850 AC: 12932 AN: 152208 Hom.: 955 Cov.: 33 AF XY: 0.0921 AC XY: 6855 AN XY: 74404

African (AFR) AF: 0.0249 AC: 1033 AN: 41550

American (AMR) AF: 0.177 AC: 2703 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0798 AC: 277 AN: 3472

East Asian (EAS) AF: 0.349 AC: 1800 AN: 5154

South Asian (SAS) AF: 0.123 AC: 592 AN: 4822

European-Finnish (FIN) AF: 0.142 AC: 1500 AN: 10588

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0698 AC: 4745 AN: 68008

Other (OTH) AF: 0.0942 AC: 199 AN: 2112

Alfa AF: 0.0783 Hom.: 1057

Bravo AF: 0.0873

Asia WGS AF: 0.219 AC: 761 AN: 3478

EpiCase AF: 0.0655

EpiControl AF: 0.0673

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	LRRK1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.20
DANN	Benign	0.77
PhyloP100		-6.3
Mutation Taster		=95/5	polymorphism (auto)

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: rs3764739; hg19: chr15-101606261; COSMIC: COSV52605416; COSMIC: COSV52605416;