rs2839158

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002340.6(LSS):c.524G>A(p.Arg175Gln) variant causes a missense change. The variant allele was found at a frequency of 0.156 in 1,613,904 control chromosomes in the GnomAD database, including 20,582 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.14 ( 1640 hom., cov: 32)

Exomes 𝑓: 0.16 ( 18942 hom. )

Consequence

LSS
NM_002340.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 5.98

Variant links:

Genes affected

LSS (HGNC:6708): (lanosterol synthase) The protein encoded by this gene catalyzes the conversion of (S)-2,3 oxidosqualene to lanosterol. The encoded protein is a member of the terpene cyclase/mutase family and catalyzes the first step in the biosynthesis of cholesterol, steroid hormones, and vitamin D. Alternative splicing results in multiple transcript variants encoding different isoforms.[provided by RefSeq, Feb 2009]

LSS links:

ENSG00000223901 (HGNC:):

ENSG00000223901 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020841062).

BP6

Variant 21-46221880-C-T is Benign according to our data. Variant chr21-46221880-C-T is described in ClinVar as [Benign]. Clinvar id is 677220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LSS	NM_002340.6 linkuse as main transcript	c.524G>A	p.Arg175Gln	missense_variant	5/22	ENST00000397728.8	NP_002331.3
LSS	NM_001001438.3 linkuse as main transcript	c.524G>A	p.Arg175Gln	missense_variant	5/23		NP_001001438.1
LSS	NM_001145436.2 linkuse as main transcript	c.491G>A	p.Arg164Gln	missense_variant	5/22		NP_001138908.1
LSS	NM_001145437.2 linkuse as main transcript	c.284G>A	p.Arg95Gln	missense_variant	4/21		NP_001138909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LSS	ENST00000397728.8 linkuse as main transcript	c.524G>A	p.Arg175Gln	missense_variant	5/22	1	NM_002340.6	ENSP00000380837.2		P48449-1

Frequencies

GnomAD3 genomes

AF:

0.143

AC:

21766

AN:

151964

Hom.:

1638

Cov.:

show subpopulations

Gnomad AFR

AF:

0.132

Gnomad AMI

AF:

0.131

Gnomad AMR

AF:

0.137

Gnomad ASJ

AF:

0.120

Gnomad EAS

AF:

0.0909

Gnomad SAS

AF:

0.0883

Gnomad FIN

AF:

0.0875

Gnomad MID

AF:

0.177

Gnomad NFE

AF:

0.169

Gnomad OTH

AF:

0.155

GnomAD3 exomes

AF:

0.136

AC:

34159

AN:

251468

Hom.:

2475

AF XY:

0.137

AC XY:

18568

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.132

Gnomad AMR exome

AF:

0.122

Gnomad ASJ exome

AF:

0.122

Gnomad EAS exome

AF:

0.0956

Gnomad SAS exome

AF:

0.0999

Gnomad FIN exome

AF:

0.0888

Gnomad NFE exome

AF:

0.166

Gnomad OTH exome

AF:

0.143

GnomAD4 exome

AF:

0.158

AC:

230576

AN:

1461822

Hom.:

18942

Cov.:

AF XY:

0.156

AC XY:

113725

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.134

Gnomad4 AMR exome

AF:

0.123

Gnomad4 ASJ exome

AF:

0.125

Gnomad4 EAS exome

AF:

0.0838

Gnomad4 SAS exome

AF:

0.103

Gnomad4 FIN exome

AF:

0.0946

Gnomad4 NFE exome

AF:

0.171

Gnomad4 OTH exome

AF:

0.151

GnomAD4 genome

AF:

0.143

AC:

21780

AN:

152082

Hom.:

1640

Cov.:

AF XY:

0.137

AC XY:

10211

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.132

Gnomad4 AMR

AF:

0.137

Gnomad4 ASJ

AF:

0.120

Gnomad4 EAS

AF:

0.0909

Gnomad4 SAS

AF:

0.0886

Gnomad4 FIN

AF:

0.0875

Gnomad4 NFE

AF:

0.169

Gnomad4 OTH

AF:

0.155

Alfa

AF:

0.160

Hom.:

5161

Bravo

AF:

0.149

TwinsUK

AF:

0.173

AC:

641

ALSPAC

AF:

0.174

AC:

669

ESP6500AA

AF:

0.135

AC:

597

ESP6500EA

AF:

0.168

AC:

1444

ExAC

AF:

0.136

AC:

16564

Asia WGS

AF:

0.105

AC:

368

AN:

3478

EpiCase

AF:

0.168

EpiControl

AF:

0.173

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

LSS-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.13

T;T;.;.;.

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

.;D;D;D;D

MetaRNN

Benign

0.0021

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

M;M;.;.;.

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-2.2

N;N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.055

T;T;D;T;D

Sift4G

Benign

0.092

T;T;T;T;T

Polyphen

0.62

P;P;.;.;.

Vest4

0.23

MPC

0.47

ClinPred

0.030

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.47

gMVP

0.71

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