rs4965778

chr15-101051718-A-Gchr15-101051718-A-T

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.3447A>G(p.Thr1149=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 1,613,162 control chromosomes in the GnomAD database, including 140,114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (12154 hom., cov: 33)
  • Exomes 𝑓: 0.41 (127960 hom.)
• Consequence: LRRK1 NM_024652.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.42

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 15-101051718-A-G is Benign according to our data. Variant chr15-101051718-A-G is described in ClinVar as [Benign]. Clinvar id is 1601184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.42 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.768 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK1	NM_024652.6	c.3447A>G	p.Thr1149=	synonymous_variant	24/34	ENST00000388948.8
LOC105371026	XR_001751726.2	n.1051-939T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK1	ENST00000388948.8	c.3447A>G	p.Thr1149=	synonymous_variant	24/34	5	NM_024652.6	P1
LRRK1	ENST00000525284.5	c.*1380A>G		3_prime_UTR_variant, NMD_transcript_variant	23/33	1
LRRK1	ENST00000531270.5	c.*1211A>G		3_prime_UTR_variant, NMD_transcript_variant	22/32	1
	ENST00000559857.1	n.673-939T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55982 AN: 151974 Hom.: 12159 Cov.: 33

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.369

Gnomad AMR AF: 0.509

Gnomad ASJ AF: 0.341

Gnomad EAS AF: 0.789

Gnomad SAS AF: 0.457

Gnomad FIN AF: 0.519

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.400

Gnomad OTH AF: 0.394

GnomAD3 exomes AF: 0.458 AC: 113567 AN: 248140 Hom.: 28788 AF XY: 0.452 AC XY: 60887 AN XY: 134654

Gnomad AFR exome AF: 0.156

Gnomad AMR exome AF: 0.623

Gnomad ASJ exome AF: 0.330

Gnomad EAS exome AF: 0.807

Gnomad SAS exome AF: 0.437

Gnomad FIN exome AF: 0.511

Gnomad NFE exome AF: 0.400

Gnomad OTH exome AF: 0.447

GnomAD4 exome AF: 0.409 AC: 597200 AN: 1461070 Hom.: 127960 Cov.: 53 AF XY: 0.410 AC XY: 297649 AN XY: 726808

Gnomad4 AFR exome AF: 0.154

Gnomad4 AMR exome AF: 0.608

Gnomad4 ASJ exome AF: 0.334

Gnomad4 EAS exome AF: 0.767

Gnomad4 SAS exome AF: 0.437

Gnomad4 FIN exome AF: 0.504

Gnomad4 NFE exome AF: 0.390

Gnomad4 OTH exome AF: 0.412

GnomAD4 genome AF: 0.368 AC: 56000 AN: 152092 Hom.: 12154 Cov.: 33 AF XY: 0.382 AC XY: 28443 AN XY: 74378

Gnomad4 AFR AF: 0.163

Gnomad4 AMR AF: 0.509

Gnomad4 ASJ AF: 0.341

Gnomad4 EAS AF: 0.789

Gnomad4 SAS AF: 0.456

Gnomad4 FIN AF: 0.519

Gnomad4 NFE AF: 0.400

Gnomad4 OTH AF: 0.392

Alfa AF: 0.391 Hom.: 7386

Bravo AF: 0.362

Asia WGS AF: 0.543 AC: 1886 AN: 3478

EpiCase AF: 0.392

EpiControl AF: 0.394

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

LRRK1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 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	-0.90
Cadd	Benign	0.045
Dann	Benign	0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs4965778; hg19: chr15-101591923; COSMIC: COSV52611809; COSMIC: COSV52611809;