rs4965778

Variant names:

• chr15-101051718-A-G
• rs4965778
• NM_024652.6:c.3447A>G

Your query was ambiguous. Multiple possible variants found:

• chr15-101051718-A-G
• chr15-101051718-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024652.6(LRRK1):​c.3447A>G​(p.Thr1149Thr) 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:3
• Conservation: PhyloP100: -2.42
• Publications: 16 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]

LRRK1-AS1 (HGNC:58299):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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.3447A>G	p.Thr1149Thr	synonymous	Exon 24 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.3447A>G	p.Thr1149Thr	synonymous	Exon 24 of 34	ENSP00000373600.3
	LRRK1	ENST00000525284.5	TSL:1	n.*1380A>G		non_coding_transcript_exon	Exon 23 of 33	ENSP00000433069.1
	LRRK1	ENST00000531270.5	TSL:1	n.*1211A>G		non_coding_transcript_exon	Exon 22 of 32	ENSP00000431668.1

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

GnomAD2 exomes AF: 0.458 AC: 113567 AN: 248140 AF XY: 0.452

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 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

African (AFR) AF: 0.154 AC: 5166 AN: 33476

American (AMR) AF: 0.608 AC: 27176 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 8727 AN: 26106

East Asian (EAS) AF: 0.767 AC: 30430 AN: 39688

South Asian (SAS) AF: 0.437 AC: 37688 AN: 86236

European-Finnish (FIN) AF: 0.504 AC: 26718 AN: 53024

Middle Eastern (MID) AF: 0.474 AC: 2732 AN: 5764

European-Non Finnish (NFE) AF: 0.390 AC: 433689 AN: 1111726

Other (OTH) AF: 0.412 AC: 24874 AN: 60360

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

African (AFR) AF: 0.163 AC: 6783 AN: 41524

American (AMR) AF: 0.509 AC: 7783 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.341 AC: 1184 AN: 3468

East Asian (EAS) AF: 0.789 AC: 4072 AN: 5164

South Asian (SAS) AF: 0.456 AC: 2200 AN: 4824

European-Finnish (FIN) AF: 0.519 AC: 5490 AN: 10588

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.400 AC: 27194 AN: 67922

Other (OTH) AF: 0.392 AC: 827 AN: 2110

Alfa AF: 0.388 Hom.: 9955

Bravo AF: 0.362

Asia WGS AF: 0.543 AC: 1886 AN: 3478

EpiCase AF: 0.392

EpiControl AF: 0.394

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	LRRK1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.045
DANN	Benign	0.43
PhyloP100		-2.4
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4965778; hg19: chr15-101591923; COSMIC: COSV52611809; COSMIC: COSV52611809;