21-46228958-A-G

Variant names:

• chr21-46228958-A-G
• rs915803
• NM_002340.6:c.-213T>C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002340.6(LSS):​c.-213T>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.483 in 559,176 control chromosomes in the GnomAD database, including 67,022 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.51 (19406 hom., cov: 23)
  • Exomes 𝑓: 0.47 (47616 hom.)
• Consequence: LSS NM_002340.6 upstream_gene
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.928

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 21-46228958-A-G is Benign according to our data. Variant chr21-46228958-A-G is described in ClinVar as [Benign]. Clinvar id is 1235098.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LSS	NM_002340.6	c.-213T>C		upstream_gene_variant		ENST00000397728.8	NP_002331.3
LSS	NM_001001438.3	c.-213T>C		upstream_gene_variant			NP_001001438.1
LSS	NM_001145436.2	c.-213T>C		upstream_gene_variant			NP_001138908.1
LSS	NM_001145437.2	c.-585T>C		upstream_gene_variant			NP_001138909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LSS	ENST00000397728.8	c.-213T>C		upstream_gene_variant		1	NM_002340.6	ENSP00000380837.2

Frequencies

GnomAD3 genomes AF: 0.507 AC: 75002 AN: 147982 Hom.: 19397 Cov.: 23

Gnomad AFR AF: 0.600

Gnomad AMI AF: 0.318

Gnomad AMR AF: 0.531

Gnomad ASJ AF: 0.438

Gnomad EAS AF: 0.322

Gnomad SAS AF: 0.472

Gnomad FIN AF: 0.431

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.478

Gnomad OTH AF: 0.496

GnomAD4 exome AF: 0.475 AC: 195252 AN: 411108 Hom.: 47616 AF XY: 0.474 AC XY: 102987 AN XY: 217242

Gnomad4 AFR exome AF: 0.599

Gnomad4 AMR exome AF: 0.564

Gnomad4 ASJ exome AF: 0.459

Gnomad4 EAS exome AF: 0.261

Gnomad4 SAS exome AF: 0.490

Gnomad4 FIN exome AF: 0.430

Gnomad4 NFE exome AF: 0.490

Gnomad4 OTH exome AF: 0.482

GnomAD4 genome AF: 0.507 AC: 75025 AN: 148068 Hom.: 19406 Cov.: 23 AF XY: 0.503 AC XY: 36257 AN XY: 72152

Gnomad4 AFR AF: 0.600

Gnomad4 AMR AF: 0.531

Gnomad4 ASJ AF: 0.438

Gnomad4 EAS AF: 0.321

Gnomad4 SAS AF: 0.472

Gnomad4 FIN AF: 0.431

Gnomad4 NFE AF: 0.478

Gnomad4 OTH AF: 0.492

Alfa AF: 0.303 Hom.: 645

Bravo AF: 0.518

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.9
DANN	Benign	0.48

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs915803; hg19: chr21-47648872;