15-101068737-AGAGTGGT-A

Variant names:

• chr15-101068737-AGAGTGGT-A
• rs886038213
• NM_024652.6:c.5939_5945delAGTGGTG

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_024652.6(LRRK1):​c.5939_5945delAGTGGTG​(p.Glu1980AlafsTer66) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LRRK1 NM_024652.6 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.99
• Publications: 3 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: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.018 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-101068737-AGAGTGGT-A is Pathogenic according to our data. Variant chr15-101068737-AGAGTGGT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 254688.Status of the report is no_assertion_criteria_provided, 0 stars.

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.5939_5945delAGTGGTG	p.Glu1980AlafsTer66	frameshift	Exon 34 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.5939_5945delAGTGGTG	p.Glu1980AlafsTer66	frameshift	Exon 34 of 34	ENSP00000373600.3
	LRRK1	ENST00000525284.5	TSL:1	n.*4065_*4071delAGTGGTG		non_coding_transcript_exon	Exon 33 of 33	ENSP00000433069.1
	LRRK1	ENST00000526457.3	TSL:1	n.*135_*141delAGTGGTG		non_coding_transcript_exon	Exon 10 of 10	ENSP00000436672.2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Osteosclerotic metaphyseal dysplasia Pathogenic:1

Dec 14, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0
Mutation Taster		=2/198	disease causing

Splicing

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

Other links and lift over

dbSNP: rs886038213; hg19: chr15-101608942;