LRRK1 p.Thr967Met

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_024652.6(LRRK1):c.2900C>T(p.Thr967Met) variant causes a missense change. The variant allele was found at a frequency of 0.000989 in 1,614,122 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. T967T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0010 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00099 ( 2 hom. )

Consequence

LRRK1
NM_024652.6 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.50

Publications

8 publications found

Variant links:

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 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_024652.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01018706).

BP6

Variant 15-101029169-C-T is Benign according to our data. Variant chr15-101029169-C-T is described in ClinVar as Benign. ClinVar VariationId is 1533558.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00101 (154/152322) while in subpopulation NFE AF = 0.000794 (54/68044). AF 95% confidence interval is 0.000625. There are 1 homozygotes in GnomAd4. There are 91 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.2900C>T	p.Thr967Met	missense	Exon 20 of 34	NP_078928.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRRK1	ENST00000388948.8	TSL:5 MANE Select	c.2900C>T	p.Thr967Met	missense	Exon 20 of 34	ENSP00000373600.3	Q38SD2-1
LRRK1	ENST00000525284.5	TSL:1	n.*833C>T		non_coding_transcript_exon	Exon 19 of 33	ENSP00000433069.1	E9PMK9
LRRK1	ENST00000531270.5	TSL:1	n.*828C>T		non_coding_transcript_exon	Exon 19 of 32	ENSP00000431668.1	E9PK39

Frequencies

GnomAD3 genomes

AF:

0.00101

AC:

154

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00819

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000794

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00120

AC:

298

AN:

249230

AF XY:

0.00134

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00757

Gnomad NFE exome

AF:

0.000964

Gnomad OTH exome

AF:

0.00165

GnomAD4 exome

AF:

0.000987

AC:

1443

AN:

1461800

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

756

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33480

American (AMR)

AF:

0.0000894

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000174

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00788

AC:

421

AN:

53396

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000862

AC:

958

AN:

1111954

Other (OTH)

AF:

0.000629

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

159

239

318

398

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00101

AC:

154

AN:

152322

Hom.:

Cov.:

AF XY:

0.00122

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41556

American (AMR)

AF:

0.000261

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00819

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000794

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000668

Hom.:

Bravo

AF:

0.000374

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000652

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.057

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.028

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.9

PhyloP100

4.5

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.90

REVEL

Benign

0.22

Sift

Benign

0.26

Sift4G

Uncertain

0.0030

Varity_R

0.077

gMVP

0.76

Mutation Taster

=94/6

polymorphism

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over