15-101049767-T-A

Variant names:

• chr15-101049767-T-A
• rs41339845
• NM_024652.6:c.3423T>A

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.3423T>A​(p.Ile1141Ile) 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:3
• Conservation: PhyloP100: -3.30
• Publications: 3 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=-0.51).
• BP6: Variant 15-101049767-T-A is Benign according to our data. Variant chr15-101049767-T-A is described in ClinVar as Benign. ClinVar VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK1	NM_024652.6	MANE Select	c.3423T>A	p.Ile1141Ile	synonymous	Exon 23 of 34	NP_078928.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK1	ENST00000388948.8	TSL:5 MANE Select	c.3423T>A	p.Ile1141Ile	synonymous	Exon 23 of 34	ENSP00000373600.3
	LRRK1	ENST00000525284.5	TSL:1	n.*1356T>A		non_coding_transcript_exon	Exon 22 of 33	ENSP00000433069.1
	LRRK1	ENST00000531270.5	TSL:1	n.*1187T>A		non_coding_transcript_exon	Exon 21 of 32	ENSP00000431668.1

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

GnomAD2 exomes AF: 0.0164 AC: 4075 AN: 248204 AF XY: 0.0143

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 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

African (AFR) AF: 0.116 AC: 3894 AN: 33444

American (AMR) AF: 0.0169 AC: 754 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.0481 AC: 1256 AN: 26106

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39676

South Asian (SAS) AF: 0.00545 AC: 469 AN: 86116

European-Finnish (FIN) AF: 0.00176 AC: 94 AN: 53418

Middle Eastern (MID) AF: 0.0253 AC: 146 AN: 5764

European-Non Finnish (NFE) AF: 0.00793 AC: 8811 AN: 1111624

Other (OTH) AF: 0.0190 AC: 1146 AN: 60366

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

African (AFR) AF: 0.114 AC: 4729 AN: 41534

American (AMR) AF: 0.0289 AC: 443 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0527 AC: 183 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4826

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10620

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00897 AC: 610 AN: 68030

Other (OTH) AF: 0.0411 AC: 87 AN: 2116

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

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	-0.51
CADD	Benign	0.55
DANN	Benign	0.75
PhyloP100		-3.3
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs41339845; hg19: chr15-101589972;