rs866257041

Variant names:

• chr21-46228813-A-C
• rs866257041
• ENST00000356396.8:c.-68T>G

Your query was ambiguous. Multiple possible variants found:

• chr21-46228813-A-C
• chr21-46228813-A-G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 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]

MCM3AP-AS1 (HGNC:16417): (MCM3AP antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000356396.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LSS	NM_002340.6	MANE Select	c.-68T>G		upstream_gene	N/A	NP_002331.3
	LSS	NM_001001438.3		c.-68T>G		upstream_gene	N/A	NP_001001438.1	P48449-1
	LSS	NM_001145436.2		c.-68T>G		upstream_gene	N/A	NP_001138908.1	P48449-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LSS	ENST00000356396.8	TSL:1	c.-68T>G		5_prime_UTR	Exon 1 of 23	ENSP00000348762.3	P48449-1
	LSS	ENST00000457828.6	TSL:1	c.-440T>G		5_prime_UTR	Exon 1 of 21	ENSP00000409191.2	P48449-2
	LSS	ENST00000908051.1		c.-68T>G		5_prime_UTR	Exon 1 of 22	ENSP00000578110.1

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

African (AFR) AF: 0.0241 AC: 570 AN: 23650

American (AMR) AF: 0.00105 AC: 32 AN: 30588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18902

East Asian (EAS) AF: 0.0000388 AC: 1 AN: 25752

South Asian (SAS) AF: 0.0000462 AC: 3 AN: 64992

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28638

Middle Eastern (MID) AF: 0.000628 AC: 2 AN: 3184

European-Non Finnish (NFE) AF: 0.00000579 AC: 5 AN: 863536

Other (OTH) AF: 0.00144 AC: 67 AN: 46368

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

African (AFR) AF: 0.0332 AC: 804 AN: 24204

American (AMR) AF: 0.00318 AC: 29 AN: 9106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2408

East Asian (EAS) AF: 0.00 AC: 0 AN: 2902

South Asian (SAS) AF: 0.00 AC: 0 AN: 2894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 192

European-Non Finnish (NFE) AF: 0.0000424 AC: 2 AN: 47198

Other (OTH) AF: 0.00545 AC: 7 AN: 1284

Alfa AF: 0.00144 Hom.: 0

Bravo AF: 0.0110

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.28
DANN	Benign	0.51
PhyloP100		-2.7
PromoterAI		-0.089	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs866257041; hg19: chr21-47648727;