21-46215262-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002340.6(LSS):c.929A>G(p.His310Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,609,986 control chromosomes in the GnomAD database, including 20,718 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1609 hom., cov: 33)

Exomes 𝑓: 0.16 ( 19109 hom. )

Consequence

LSS
NM_002340.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0240

Publications

16 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=0.0022788644).

BP6

Variant 21-46215262-T-C is Benign according to our data. Variant chr21-46215262-T-C is described in ClinVar as Benign. ClinVar VariationId is 677221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

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.929A>G	p.His310Arg	missense	Exon 9 of 22	NP_002331.3
LSS	NM_001001438.3		c.929A>G	p.His310Arg	missense	Exon 9 of 23	NP_001001438.1	P48449-1
LSS	NM_001145436.2		c.896A>G	p.His299Arg	missense	Exon 9 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.929A>G	p.His310Arg	missense	Exon 9 of 22	ENSP00000380837.2	P48449-1
LSS	ENST00000356396.8	TSL:1	c.929A>G	p.His310Arg	missense	Exon 9 of 23	ENSP00000348762.3	P48449-1
LSS	ENST00000457828.6	TSL:1	c.689A>G	p.His230Arg	missense	Exon 8 of 21	ENSP00000409191.2	P48449-2

Frequencies

GnomAD3 genomes

AF:

0.141

AC:

21378

AN:

152054

Hom.:

1607

Cov.:

show subpopulations

Gnomad AFR

AF:

0.120

Gnomad AMI

AF:

0.130

Gnomad AMR

AF:

0.138

Gnomad ASJ

AF:

0.120

Gnomad EAS

AF:

0.0916

Gnomad SAS

AF:

0.0897

Gnomad FIN

AF:

0.0883

Gnomad MID

AF:

0.171

Gnomad NFE

AF:

0.170

Gnomad OTH

AF:

0.157

GnomAD2 exomes

AF:

0.136

AC:

33684

AN:

247726

AF XY:

0.137

show subpopulations

Gnomad AFR exome

AF:

0.121

Gnomad AMR exome

AF:

0.123

Gnomad ASJ exome

AF:

0.120

Gnomad EAS exome

AF:

0.0958

Gnomad FIN exome

AF:

0.0873

Gnomad NFE exome

AF:

0.168

Gnomad OTH exome

AF:

0.144

GnomAD4 exome

AF:

0.158

AC:

230921

AN:

1457814

Hom.:

19109

Cov.:

AF XY:

0.157

AC XY:

113918

AN XY:

725304

show subpopulations

African (AFR)

AF:

0.121

AC:

4053

AN:

33428

American (AMR)

AF:

0.123

AC:

5501

AN:

44628

Ashkenazi Jewish (ASJ)

AF:

0.124

AC:

3248

AN:

26104

East Asian (EAS)

AF:

0.0843

AC:

3344

AN:

39690

South Asian (SAS)

AF:

0.104

AC:

8938

AN:

86078

European-Finnish (FIN)

AF:

0.0935

AC:

4853

AN:

51878

Middle Eastern (MID)

AF:

0.174

AC:

771

AN:

4426

European-Non Finnish (NFE)

AF:

0.172

AC:

191105

AN:

1111404

Other (OTH)

AF:

0.151

AC:

9108

AN:

60178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

9825

19651

29476

39302

49127

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6698

13396

20094

26792

33490

<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:

0.141

AC:

21395

AN:

152172

Hom.:

1609

Cov.:

AF XY:

0.135

AC XY:

10060

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.120

AC:

5002

AN:

41520

American (AMR)

AF:

0.138

AC:

2108

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.120

AC:

416

AN:

3470

East Asian (EAS)

AF:

0.0917

AC:

473

AN:

5160

South Asian (SAS)

AF:

0.0900

AC:

434

AN:

4824

European-Finnish (FIN)

AF:

0.0883

AC:

938

AN:

10622

Middle Eastern (MID)

AF:

0.156

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.170

AC:

11525

AN:

67972

Other (OTH)

AF:

0.158

AC:

334

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

987

1974

2961

3948

4935

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

236

472

708

944

1180

<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:

0.158

Hom.:

6080

Bravo

AF:

0.145

TwinsUK

AF:

0.173

AC:

642

ALSPAC

AF:

0.174

AC:

670

ESP6500AA

AF:

0.126

AC:

556

ESP6500EA

AF:

0.169

AC:

1450

ExAC

AF:

0.136

AC:

16473

Asia WGS

AF:

0.106

AC:

370

AN:

3478

EpiCase

AF:

0.169

EpiControl

AF:

0.175

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

LSS-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

1.3

(source)

DANN

Benign

0.38

DEOGEN2

Benign

0.023

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.52

MetaRNN

Benign

0.0023

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.7

PhyloP100

-0.024

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.42

REVEL

Benign

0.028

Sift

Benign

0.35

Sift4G

Benign

0.36

Polyphen

0.0

Vest4

0.056

MPC

0.35

ClinPred

0.0029

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.54

Mutation Taster

=100/0

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