21-46228813-A-C

Position:

• chr21-46228813-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000356396.8(LSS):​c.-68T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,202,866 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (14 hom., cov: 30)
  • Exomes 𝑓: 0.00062 (12 hom.)
• Consequence: LSS ENST00000356396.8 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.70

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 21-46228813-A-C is Benign according to our data. Variant chr21-46228813-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 1186122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00866 (842/97256) while in subpopulation AFR AF= 0.0332 (804/24204). AF 95% confidence interval is 0.0313. There are 14 homozygotes in gnomad4. There are 398 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LSS	NM_002340.6	c.-68T>G		upstream_gene_variant		ENST00000397728.8	NP_002331.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LSS	ENST00000397728.8	c.-68T>G		upstream_gene_variant		1	NM_002340.6	ENSP00000380837.2

Frequencies

GnomAD3 genomes AF: 0.00866 AC: 842 AN: 97202 Hom.: 14 Cov.: 30

Gnomad AFR AF: 0.0333

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00319

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000424

Gnomad OTH AF: 0.00549

GnomAD4 exome AF: 0.000615 AC: 680 AN: 1105610 Hom.: 12 Cov.: 23 AF XY: 0.000516 AC XY: 282 AN XY: 546684

Gnomad4 AFR exome AF: 0.0241

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000388

Gnomad4 SAS exome AF: 0.0000462

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000579

Gnomad4 OTH exome AF: 0.00144

GnomAD4 genome AF: 0.00866 AC: 842 AN: 97256 Hom.: 14 Cov.: 30 AF XY: 0.00849 AC XY: 398 AN XY: 46882

Gnomad4 AFR AF: 0.0332

Gnomad4 AMR AF: 0.00318

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000424

Gnomad4 OTH AF: 0.00545

Alfa AF: 0.00144 Hom.: 0

Bravo AF: 0.0110

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.28
DANN	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs866257041; hg19: chr21-47648727;