chr15-100973841-C-T

Variant names:

• chr15-100973841-C-T
• rs377386363
• NM_024652.6:c.135C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_024652.6(LRRK1):​c.135C>T​(p.Gly45Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000195 in 1,294,202 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (2 hom.)
• Consequence: LRRK1 NM_024652.6 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.480
• Publications: 0 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]

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 15-100973841-C-T is Benign according to our data. Variant chr15-100973841-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1652793.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.48 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00021 (32/152362) while in subpopulation EAS AF = 0.00174 (9/5184). AF 95% confidence interval is 0.000905. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.135C>T	p.Gly45Gly	synonymous	Exon 3 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.135C>T	p.Gly45Gly	synonymous	Exon 3 of 34	ENSP00000373600.3	Q38SD2-1
	LRRK1	ENST00000532029.6	TSL:1	c.135C>T	p.Gly45Gly	synonymous	Exon 3 of 6	ENSP00000433268.2	Q38SD2-2
	LRRK1	ENST00000525284.5	TSL:1	n.135C>T		non_coding_transcript_exon	Exon 2 of 33	ENSP00000433069.1	E9PMK9

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000335 AC: 2 AN: 5974 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000401

Gnomad NFE exome AF: 0.000654

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000194 AC: 221 AN: 1141840 Hom.: 2 Cov.: 30 AF XY: 0.000173 AC XY: 95 AN XY: 548084

African (AFR) AF: 0.0000856 AC: 2 AN: 23362

American (AMR) AF: 0.00 AC: 0 AN: 9290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15546

East Asian (EAS) AF: 0.000747 AC: 20 AN: 26780

South Asian (SAS) AF: 0.00 AC: 0 AN: 38528

European-Finnish (FIN) AF: 0.0000994 AC: 3 AN: 30180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3100

European-Non Finnish (NFE) AF: 0.000160 AC: 152 AN: 949206

Other (OTH) AF: 0.000960 AC: 44 AN: 45848

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152362 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74512

African (AFR) AF: 0.0000481 AC: 2 AN: 41594

American (AMR) AF: 0.000196 AC: 3 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68018

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000204

Asia WGS AF: 0.00434 AC: 15 AN: 3474

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.5
DANN	Benign	0.93
PhyloP100		-0.48
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs377386363; hg19: chr15-101514046;