NM_002340.6:c.-213T>C

Variant names:

• chr21-46228958-A-G
• rs915803
• ENST00000748155.1:n.106+459A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 publications found

Genes affected

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

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]

LSS Gene-Disease associations (from GenCC):

• alopecia-intellectual disability syndrome 4

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• cataract 44

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypotrichosis 14

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• hypotrichosis simplex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive palmoplantar keratoderma and congenital alopecia

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002340.6. 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.-213T>C		upstream_gene	N/A	NP_002331.3
	LSS	NM_001001438.3		c.-213T>C		upstream_gene	N/A	NP_001001438.1	P48449-1
	LSS	NM_001145436.2		c.-213T>C		upstream_gene	N/A	NP_001138908.1	P48449-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM3AP-AS1	ENST00000748155.1		n.106+459A>G		intron	N/A
	LSS	ENST00000397728.8	TSL:1 MANE Select	c.-213T>C		upstream_gene	N/A	ENSP00000380837.2	P48449-1
	LSS	ENST00000356396.8	TSL:1	c.-213T>C		upstream_gene	N/A	ENSP00000348762.3	P48449-1

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

African (AFR) AF: 0.599 AC: 4766 AN: 7952

American (AMR) AF: 0.564 AC: 7106 AN: 12602

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 5461 AN: 11902

East Asian (EAS) AF: 0.261 AC: 6407 AN: 24592

South Asian (SAS) AF: 0.490 AC: 19736 AN: 40294

European-Finnish (FIN) AF: 0.430 AC: 12368 AN: 28780

Middle Eastern (MID) AF: 0.466 AC: 859 AN: 1842

European-Non Finnish (NFE) AF: 0.490 AC: 127086 AN: 259360

Other (OTH) AF: 0.482 AC: 11463 AN: 23784

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

African (AFR) AF: 0.600 AC: 24236 AN: 40402

American (AMR) AF: 0.531 AC: 7978 AN: 15012

Ashkenazi Jewish (ASJ) AF: 0.438 AC: 1502 AN: 3426

East Asian (EAS) AF: 0.321 AC: 1568 AN: 4878

South Asian (SAS) AF: 0.472 AC: 2164 AN: 4588

European-Finnish (FIN) AF: 0.431 AC: 4269 AN: 9916

Middle Eastern (MID) AF: 0.493 AC: 140 AN: 284

European-Non Finnish (NFE) AF: 0.478 AC: 31870 AN: 66608

Other (OTH) AF: 0.492 AC: 1015 AN: 2064

Alfa AF: 0.303 Hom.: 645

Bravo AF: 0.518

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.9
DANN	Benign	0.48
PhyloP100		-0.93
PromoterAI		0.073	Neutral

Splicing

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

Other links and lift over

dbSNP: rs915803; hg19: chr21-47648872;