rs16978976

Positions:

• chr21-46206814-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002340.6(LSS):​c.1468-46G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0773 in 1,435,124 control chromosomes in the GnomAD database, including 4,820 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (332 hom., cov: 33)
  • Exomes 𝑓: 0.080 (4488 hom.)
• Consequence: LSS NM_002340.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.747

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 21-46206814-C-T is Benign according to our data. Variant chr21-46206814-C-T is described in ClinVar as [Benign]. Clinvar id is 1276794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0839 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LSS	NM_002340.6	c.1468-46G>A		intron_variant		ENST00000397728.8	NP_002331.3
LSS	NM_001001438.3	c.1468-46G>A		intron_variant			NP_001001438.1
LSS	NM_001145436.2	c.1435-46G>A		intron_variant			NP_001138908.1
LSS	NM_001145437.2	c.1228-46G>A		intron_variant			NP_001138909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LSS	ENST00000397728.8	c.1468-46G>A		intron_variant		1	NM_002340.6	ENSP00000380837.2
LSS	ENST00000356396.8	c.1468-46G>A		intron_variant		1		ENSP00000348762.3
LSS	ENST00000457828.6	c.1228-46G>A		intron_variant		1		ENSP00000409191.2
LSS	ENST00000522411.5	c.1435-46G>A		intron_variant		2		ENSP00000429133.1

Frequencies

GnomAD3 genomes AF: 0.0545 AC: 8295 AN: 152148 Hom.: 332 Cov.: 33

Gnomad AFR AF: 0.0182

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0474

Gnomad ASJ AF: 0.0522

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0333

Gnomad FIN AF: 0.0406

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0857

Gnomad OTH AF: 0.0635

GnomAD3 exomes AF: 0.0564 AC: 13492 AN: 239174 Hom.: 507 AF XY: 0.0587 AC XY: 7645 AN XY: 130182

Gnomad AFR exome AF: 0.0180

Gnomad AMR exome AF: 0.0344

Gnomad ASJ exome AF: 0.0545

Gnomad EAS exome AF: 0.000221

Gnomad SAS exome AF: 0.0376

Gnomad FIN exome AF: 0.0405

Gnomad NFE exome AF: 0.0848

Gnomad OTH exome AF: 0.0629

GnomAD4 exome AF: 0.0800 AC: 102614 AN: 1282858 Hom.: 4488 Cov.: 19 AF XY: 0.0786 AC XY: 50927 AN XY: 647744

Gnomad4 AFR exome AF: 0.0156

Gnomad4 AMR exome AF: 0.0354

Gnomad4 ASJ exome AF: 0.0535

Gnomad4 EAS exome AF: 0.000309

Gnomad4 SAS exome AF: 0.0391

Gnomad4 FIN exome AF: 0.0416

Gnomad4 NFE exome AF: 0.0938

Gnomad4 OTH exome AF: 0.0711

GnomAD4 genome AF: 0.0545 AC: 8294 AN: 152266 Hom.: 332 Cov.: 33 AF XY: 0.0515 AC XY: 3835 AN XY: 74446

Gnomad4 AFR AF: 0.0183

Gnomad4 AMR AF: 0.0473

Gnomad4 ASJ AF: 0.0522

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0334

Gnomad4 FIN AF: 0.0406

Gnomad4 NFE AF: 0.0857

Gnomad4 OTH AF: 0.0629

Alfa AF: 0.0645 Hom.: 78

Bravo AF: 0.0535

Asia WGS AF: 0.0240 AC: 85 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.72
DANN	Benign	0.55

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

Other links and lift over

dbSNP: rs16978976; hg19: chr21-47626728;