rs41339845

chr15-101049767-T-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024652.6(LRRK1):c.3423T>A(p.Ile1141=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,613,440 control chromosomes in the GnomAD database, including 624 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (301 hom., cov: 32)
  • Exomes 𝑓: 0.011 (323 hom.)
• Consequence: LRRK1 NM_024652.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.30

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]

LOC105371026 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 15-101049767-T-A is Benign according to our data. Variant chr15-101049767-T-A is described in ClinVar as [Benign]. Clinvar id is 1599784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK1	NM_024652.6	c.3423T>A	p.Ile1141=	synonymous_variant	23/34	ENST00000388948.8
LOC105371026	XR_001751726.2	n.1197-103A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK1	ENST00000388948.8	c.3423T>A	p.Ile1141=	synonymous_variant	23/34	5	NM_024652.6	P1
LRRK1	ENST00000525284.5	c.*1356T>A		3_prime_UTR_variant, NMD_transcript_variant	22/33	1
LRRK1	ENST00000531270.5	c.*1187T>A		3_prime_UTR_variant, NMD_transcript_variant	21/32	1

Frequencies

GnomAD3 genomes AF: 0.0403 AC: 6127 AN: 152172 Hom.: 300 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.0429

Gnomad AMR AF: 0.0290

Gnomad ASJ AF: 0.0527

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00897

Gnomad OTH AF: 0.0415

GnomAD3 exomes AF: 0.0164 AC: 4075 AN: 248204 Hom.: 146 AF XY: 0.0143 AC XY: 1930 AN XY: 134722

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.0158

Gnomad ASJ exome AF: 0.0467

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00510

Gnomad FIN exome AF: 0.00167

Gnomad NFE exome AF: 0.00851

Gnomad OTH exome AF: 0.0177

GnomAD4 exome AF: 0.0113 AC: 16571 AN: 1461150 Hom.: 323 Cov.: 31 AF XY: 0.0110 AC XY: 8019 AN XY: 726828

Gnomad4 AFR exome AF: 0.116

Gnomad4 AMR exome AF: 0.0169

Gnomad4 ASJ exome AF: 0.0481

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00545

Gnomad4 FIN exome AF: 0.00176

Gnomad4 NFE exome AF: 0.00793

Gnomad4 OTH exome AF: 0.0190

GnomAD4 genome AF: 0.0403 AC: 6138 AN: 152290 Hom.: 301 Cov.: 32 AF XY: 0.0384 AC XY: 2858 AN XY: 74462

Gnomad4 AFR AF: 0.114

Gnomad4 AMR AF: 0.0289

Gnomad4 ASJ AF: 0.0527

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00897

Gnomad4 OTH AF: 0.0411

Alfa AF: 0.0199 Hom.: 26

Bravo AF: 0.0453

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.0101

EpiControl AF: 0.0117

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

LRRK1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	0.55
Dann	Benign	0.75

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: rs41339845; hg19: chr15-101589972;