Genetic Variant LSS:p.Pro688Leu (chr21-46191885-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002340.6(LSS):c.2063C>T(p.Pro688Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0174 in 1,612,632 control chromosomes in the GnomAD database, including 291 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. P688P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.013 ( 14 hom., cov: 33)

Exomes 𝑓: 0.018 ( 277 hom. )

Consequence

LSS
NM_002340.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.54

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

alopecia-intellectual disability syndrome 4
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
cataract 44
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
hypotrichosis 14
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
hypotrichosis simplex
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
total early-onset cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive palmoplantar keratoderma and congenital alopecia
Inheritance: AR Classification: LIMITED Submitted by: G2P

LSS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009421557).

BP6

Variant 21-46191885-G-A is Benign according to our data. Variant chr21-46191885-G-A is described in ClinVar as Benign. ClinVar VariationId is 668540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0127 (1937/152300) while in subpopulation SAS AF = 0.0228 (110/4828). AF 95% confidence interval is 0.0193. There are 14 homozygotes in GnomAd4. There are 929 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002340.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LSS	NM_002340.6	MANE Select	c.2063C>T	p.Pro688Leu	missense	Exon 21 of 22	NP_002331.3
LSS	NM_001001438.3		c.2063C>T	p.Pro688Leu	missense	Exon 21 of 23	NP_001001438.1	P48449-1
LSS	NM_001145436.2		c.2030C>T	p.Pro677Leu	missense	Exon 21 of 22	NP_001138908.1	P48449-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LSS	ENST00000397728.8	TSL:1 MANE Select	c.2063C>T	p.Pro688Leu	missense	Exon 21 of 22	ENSP00000380837.2	P48449-1
LSS	ENST00000356396.8	TSL:1	c.2063C>T	p.Pro688Leu	missense	Exon 21 of 23	ENSP00000348762.3	P48449-1
LSS	ENST00000457828.6	TSL:1	c.1823C>T	p.Pro608Leu	missense	Exon 20 of 21	ENSP00000409191.2	P48449-2

Frequencies

GnomAD3 genomes

AF:

0.0127

AC:

1936

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00335

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0101

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0224

Gnomad FIN

AF:

0.0110

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0195

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.0158

AC:

3920

AN:

247854

AF XY:

0.0174

show subpopulations

Gnomad AFR exome

AF:

0.00260

Gnomad AMR exome

AF:

0.00751

Gnomad ASJ exome

AF:

0.0138

Gnomad EAS exome

AF:

0.000381

Gnomad FIN exome

AF:

0.0137

Gnomad NFE exome

AF:

0.0207

Gnomad OTH exome

AF:

0.0147

GnomAD4 exome

AF:

0.0179

AC:

26123

AN:

1460332

Hom.:

277

Cov.:

AF XY:

0.0185

AC XY:

13432

AN XY:

726240

show subpopulations

African (AFR)

AF:

0.00251

AC:

AN:

33456

American (AMR)

AF:

0.00773

AC:

345

AN:

44604

Ashkenazi Jewish (ASJ)

AF:

0.0130

AC:

339

AN:

26096

East Asian (EAS)

AF:

0.000151

AC:

AN:

39688

South Asian (SAS)

AF:

0.0241

AC:

2072

AN:

85870

European-Finnish (FIN)

AF:

0.0144

AC:

766

AN:

53196

Middle Eastern (MID)

AF:

0.0191

AC:

110

AN:

5762

European-Non Finnish (NFE)

AF:

0.0193

AC:

21441

AN:

1111316

Other (OTH)

AF:

0.0159

AC:

960

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

1242

2484

3725

4967

6209

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

762

1524

2286

3048

3810

<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:

0.0127

AC:

1937

AN:

152300

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

929

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00334

AC:

139

AN:

41560

American (AMR)

AF:

0.0101

AC:

154

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0127

AC:

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.0228

AC:

110

AN:

4828

European-Finnish (FIN)

AF:

0.0110

AC:

117

AN:

10620

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0195

AC:

1328

AN:

68028

Other (OTH)

AF:

0.0104

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

101

203

304

406

507

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0180

Hom.:

Bravo

AF:

0.0120

TwinsUK

AF:

0.0202

AC:

ALSPAC

AF:

0.0192

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0214

AC:

184

ExAC

AF:

0.0161

AC:

1955

Asia WGS

AF:

0.00895

AC:

AN:

3478

EpiCase

AF:

0.0203

EpiControl

AF:

0.0206

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.17

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.0094

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

PhyloP100

3.5

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-6.5

REVEL

Uncertain

0.33

Sift

Benign

0.51

Sift4G

Benign

0.27

Polyphen

1.0

Vest4

0.13

MPC

0.95

ClinPred

0.031

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.62

gMVP

0.68

Mutation Taster

=52/48

polymorphism (auto)

(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

Publications

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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