Variant 15-100973831-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024652.6(LRRK1):c.125C>T(p.Ser42Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000175 in 1,141,138 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000018 ( 0 hom. )

Consequence

LRRK1
NM_024652.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.20

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRK1	NM_024652.6 linkuse as main transcript	c.125C>T	p.Ser42Phe	missense_variant	3/34	ENST00000388948.8	NP_078928.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRK1	ENST00000388948.8 linkuse as main transcript	c.125C>T	p.Ser42Phe	missense_variant	3/34	5	NM_024652.6	ENSP00000373600	P1	Q38SD2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000175

AC:

AN:

1141138

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

547766

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000211

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 27, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with LRRK1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 42 of the LRRK1 protein (p.Ser42Phe). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.017

T;.

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.74

T;T

M_CAP

Uncertain

0.087

MetaRNN

Uncertain

0.44

T;T

MetaSVM

Benign

-0.36

MutationAssessor

Benign

2.0

M;M

MutationTaster

Benign

0.96

N;N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.18

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.97

D;D

Vest4

0.33

MutPred

0.26

Loss of glycosylation at S42 (P = 0.0077);Loss of glycosylation at S42 (P = 0.0077);

MVP

0.90

MPC

1.2

ClinPred

0.90

GERP RS

5.6

Varity_R

0.20

gMVP

0.26

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over