15-100973810-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024652.6(LRRK1):c.104G>A(p.Gly35Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000877 in 1,139,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.8e-7 (0 hom.)
• Consequence: LRRK1 NM_024652.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0110

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.020769477).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK1	NM_024652.6	c.104G>A	p.Gly35Glu	missense_variant	3/34	ENST00000388948.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK1	ENST00000388948.8	c.104G>A	p.Gly35Glu	missense_variant	3/34	5	NM_024652.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.77e-7 AC: 1 AN: 1139914 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 547346

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000218

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2023

The c.104G>A (p.G35E) alteration is located in exon 3 (coding exon 2) of the LRRK1 gene. This alteration results from a G to A substitution at nucleotide position 104, causing the glycine (G) at amino acid position 35 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	2.8
Dann	Benign	0.94
DEOGEN2	Benign	0.013	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.021	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.14	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.20	N;N
REVEL	Benign	0.11
Sift	Benign	0.98	T;T
Sift4G	Benign	0.30	T;T
Polyphen		0.0	B;B
Vest4		0.060
MutPred		0.11		Loss of MoRF binding (P = 0.0564);Loss of MoRF binding (P = 0.0564);
MVP		0.52
MPC		0.52
ClinPred		0.061	T
GERP RS		-5.9
Varity_R		0.061
gMVP		0.16

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: rs1011877404; hg19: chr15-101514015;