15-100924709-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.77G>A(p.Arg26His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R26C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: LRRK1 NM_024652.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.215

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=0.06676933).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK1	NM_024652.6	c.77G>A	p.Arg26His	missense_variant	2/34	ENST00000388948.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK1	ENST00000388948.8	c.77G>A	p.Arg26His	missense_variant	2/34	5	NM_024652.6	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251154 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135780

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461814 Hom.: 0 Cov.: 30 AF XY: 0.0000165 AC XY: 12 AN XY: 727216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 17, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with LRRK1-related conditions. This variant is present in population databases (rs756110175, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 26 of the LRRK1 protein (p.Arg26His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	7.6
Dann	Uncertain	0.99
DEOGEN2	Benign	0.013	T;.;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.55	T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.067	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N;.;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.11	N;N;N
REVEL	Benign	0.045
Sift	Benign	0.16	T;T;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.033
MutPred		0.30		Gain of catalytic residue at M28 (P = 0.0402);Gain of catalytic residue at M28 (P = 0.0402);Gain of catalytic residue at M28 (P = 0.0402);
MVP		0.70
MPC		0.50
ClinPred		0.048	T
GERP RS		-1.8
Varity_R		0.042
gMVP		0.12

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: rs756110175; hg19: chr15-101464914;