chr21-46206814-C-T

Variant names:

• chr21-46206814-C-T
• rs16978976
• NM_002340.6:c.1468-46G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 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]

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 -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 VariationId 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LSS	NM_002340.6	MANE Select	c.1468-46G>A		intron	N/A	NP_002331.3
	LSS	NM_001001438.3		c.1468-46G>A		intron	N/A	NP_001001438.1
	LSS	NM_001145436.2		c.1435-46G>A		intron	N/A	NP_001138908.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LSS	ENST00000397728.8	TSL:1 MANE Select	c.1468-46G>A		intron	N/A	ENSP00000380837.2
	LSS	ENST00000356396.8	TSL:1	c.1468-46G>A		intron	N/A	ENSP00000348762.3
	LSS	ENST00000457828.6	TSL:1	c.1228-46G>A		intron	N/A	ENSP00000409191.2

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

GnomAD2 exomes AF: 0.0564 AC: 13492 AN: 239174 AF XY: 0.0587

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 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

African (AFR) AF: 0.0156 AC: 469 AN: 30040

American (AMR) AF: 0.0354 AC: 1571 AN: 44386

Ashkenazi Jewish (ASJ) AF: 0.0535 AC: 1337 AN: 25008

East Asian (EAS) AF: 0.000309 AC: 12 AN: 38894

South Asian (SAS) AF: 0.0391 AC: 3241 AN: 82820

European-Finnish (FIN) AF: 0.0416 AC: 1756 AN: 42252

Middle Eastern (MID) AF: 0.0736 AC: 401 AN: 5450

European-Non Finnish (NFE) AF: 0.0938 AC: 89931 AN: 959226

Other (OTH) AF: 0.0711 AC: 3896 AN: 54782

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

African (AFR) AF: 0.0183 AC: 759 AN: 41548

American (AMR) AF: 0.0473 AC: 724 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0522 AC: 181 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.0334 AC: 161 AN: 4824

European-Finnish (FIN) AF: 0.0406 AC: 431 AN: 10612

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0857 AC: 5830 AN: 68008

Other (OTH) AF: 0.0629 AC: 133 AN: 2116

Alfa AF: 0.0650 Hom.: 122

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 21, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.72
DANN	Benign	0.55
PhyloP100		-0.75
Mutation Taster		=100/0	polymorphism (auto)

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: rs16978976; hg19: chr21-47626728;