15-101066056-C-A

Variant names:

• chr15-101066056-C-A
• NM_024652.6:c.5619C>A
• LRRK1 p.Thr1873Thr

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024652.6(LRRK1):​c.5619C>A​(p.Thr1873Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars). Synonymous variant affecting the same amino acid position (i.e. T1873T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LRRK1 NM_024652.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -6.26
• Publications: 0 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]

LRRK1-AS1 (HGNC:58299):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

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

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK1	ENST00000388948.8	TSL:5 MANE Select	c.5619C>A	p.Thr1873Thr	synonymous	Exon 32 of 34	ENSP00000373600.3	Q38SD2-1
	LRRK1	ENST00000525284.5	TSL:1	n.*3745C>A		non_coding_transcript_exon	Exon 31 of 33	ENSP00000433069.1	E9PMK9
	LRRK1	ENST00000526457.3	TSL:1	n.1647C>A		non_coding_transcript_exon	Exon 7 of 10	ENSP00000436672.2	H0YEW1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.60
DANN	Benign	0.66
PhyloP100		-6.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.36		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr15-101606261;