rs11558754

chr21-46222695-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002340.6(LSS):c.363C>T(p.Ala121=) 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:3
• Conservation: PhyloP100: -4.17

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
LSS	NM_002340.6	c.363C>T	p.Ala121=	synonymous_variant	4/22	ENST00000397728.8
LSS	NM_001001438.3	c.363C>T	p.Ala121=	synonymous_variant	4/23
LSS	NM_001145436.2	c.363C>T	p.Ala121=	synonymous_variant	4/22
LSS	NM_001145437.2	c.123C>T	p.Ala41=	synonymous_variant	3/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LSS	ENST00000397728.8	c.363C>T	p.Ala121=	synonymous_variant	4/22	1	NM_002340.6	P1
	ENST00000626933.1	n.366+701G>A		intron_variant, non_coding_transcript_variant		5

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

GnomAD3 exomes AF: 0.136 AC: 34011 AN: 250330 Hom.: 2441 AF XY: 0.137 AC XY: 18485 AN XY: 135382

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 SAS exome AF: 0.0998

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

Gnomad4 AFR exome AF: 0.134

Gnomad4 AMR exome AF: 0.123

Gnomad4 ASJ exome AF: 0.124

Gnomad4 EAS exome AF: 0.0899

Gnomad4 SAS exome AF: 0.103

Gnomad4 FIN exome AF: 0.0945

Gnomad4 NFE exome AF: 0.171

Gnomad4 OTH exome AF: 0.151

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

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.120

Gnomad4 EAS AF: 0.0985

Gnomad4 SAS AF: 0.0892

Gnomad4 FIN AF: 0.0881

Gnomad4 NFE AF: 0.169

Gnomad4 OTH AF: 0.154

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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	Invitae	Jan 31, 2024	- -

LSS-related disorder Benign:1

Benign, criteria provided, single submitter

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
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.55
Dann	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

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