rs11558754

Variant names:

• chr21-46222695-G-A
• rs11558754
• NM_002340.6:c.363C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002340.6(LSS):​c.363C>T​(p.Ala121Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,613,614 control chromosomes in the GnomAD database, including 20,596 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1646 hom., cov: 34)
  • Exomes 𝑓: 0.16 (18950 hom.)
• Consequence: LSS NM_002340.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.17
• Publications: 8 publications found

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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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

ENSG00000223901 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 21-46222695-G-A is Benign according to our data. Variant chr21-46222695-G-A is described in ClinVar as Benign. ClinVar VariationId is 677219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.18 with no splicing effect.
• 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 rank	MANE	Protein	UniProt
LSS	NM_002340.6	c.363C>T	p.Ala121Ala	synonymous_variant	Exon 4 of 22	ENST00000397728.8	NP_002331.3
LSS	NM_001001438.3	c.363C>T	p.Ala121Ala	synonymous_variant	Exon 4 of 23		NP_001001438.1
LSS	NM_001145436.2	c.363C>T	p.Ala121Ala	synonymous_variant	Exon 4 of 22		NP_001138908.1
LSS	NM_001145437.2	c.123C>T	p.Ala41Ala	synonymous_variant	Exon 3 of 21		NP_001138909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LSS	ENST00000397728.8	c.363C>T	p.Ala121Ala	synonymous_variant	Exon 4 of 22	1	NM_002340.6	ENSP00000380837.2

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21859 AN: 152176 Hom.: 1644 Cov.: 34

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.0987

Gnomad SAS AF: 0.0890

Gnomad FIN AF: 0.0881

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.154

GnomAD2 exomes AF: 0.136 AC: 34011 AN: 250330 AF XY: 0.137

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.121

Gnomad EAS exome AF: 0.101

Gnomad FIN exome AF: 0.0881

Gnomad NFE exome AF: 0.166

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.158 AC: 230683 AN: 1461320 Hom.: 18950 Cov.: 32 AF XY: 0.157 AC XY: 113788 AN XY: 726954

African (AFR) AF: 0.134 AC: 4498 AN: 33474

American (AMR) AF: 0.123 AC: 5487 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 3253 AN: 26132

East Asian (EAS) AF: 0.0899 AC: 3568 AN: 39698

South Asian (SAS) AF: 0.103 AC: 8904 AN: 86250

European-Finnish (FIN) AF: 0.0945 AC: 5014 AN: 53070

Middle Eastern (MID) AF: 0.176 AC: 1016 AN: 5768

European-Non Finnish (NFE) AF: 0.171 AC: 189797 AN: 1111834

Other (OTH) AF: 0.151 AC: 9146 AN: 60384

GnomAD4 genome AF: 0.144 AC: 21875 AN: 152294 Hom.: 1646 Cov.: 34 AF XY: 0.138 AC XY: 10270 AN XY: 74454

African (AFR) AF: 0.133 AC: 5527 AN: 41560

American (AMR) AF: 0.137 AC: 2097 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 417 AN: 3472

East Asian (EAS) AF: 0.0985 AC: 510 AN: 5176

South Asian (SAS) AF: 0.0892 AC: 431 AN: 4830

European-Finnish (FIN) AF: 0.0881 AC: 936 AN: 10622

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.169 AC: 11465 AN: 68014

Other (OTH) AF: 0.154 AC: 325 AN: 2114

Alfa AF: 0.155 Hom.: 801

Bravo AF: 0.149

Asia WGS AF: 0.106 AC: 370 AN: 3478

EpiCase AF: 0.167

EpiControl AF: 0.173

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Mar 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

LSS-related disorder Benign:1

Jul 15, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.55
DANN	Benign	0.90
PhyloP100		-4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11558754; hg19: chr21-47642609; COSMIC: COSV62701950; COSMIC: COSV62701950;