chr21-46191025-TG-T

Variant names:

• chr21-46191025-TG-T
• rs142247529
• NM_002340.6:c.*78delC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_002340.6(LSS):​c.*78delC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0191 in 1,555,320 control chromosomes in the GnomAD database, including 1,204 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.048 (430 hom., cov: 32)
  • Exomes 𝑓: 0.016 (774 hom.)
• Consequence: LSS NM_002340.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.116
• 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]

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 -10 ACMG points.

• BP6: Variant 21-46191025-TG-T is Benign according to our data. Variant chr21-46191025-TG-T is described in ClinVar as Benign. ClinVar VariationId is 1291872.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.132 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.*78delC		3_prime_UTR	Exon 22 of 22	NP_002331.3
	LSS	NM_001145436.2		c.*78delC		3_prime_UTR	Exon 22 of 22	NP_001138908.1	P48449-3
	LSS	NM_001145437.2		c.*78delC		3_prime_UTR	Exon 21 of 21	NP_001138909.1	P48449-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LSS	ENST00000397728.8	TSL:1 MANE Select	c.*78delC		3_prime_UTR	Exon 22 of 22	ENSP00000380837.2	P48449-1
	LSS	ENST00000457828.6	TSL:1	c.*78delC		3_prime_UTR	Exon 21 of 21	ENSP00000409191.2	P48449-2
	LSS	ENST00000356396.8	TSL:1	c.*38+40delC		intron	N/A	ENSP00000348762.3	P48449-1

Frequencies

GnomAD3 genomes AF: 0.0476 AC: 7232 AN: 152048 Hom.: 420 Cov.: 32

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0259

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00541

Gnomad SAS AF: 0.0867

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.00870

Gnomad OTH AF: 0.0474

GnomAD4 exome AF: 0.0160 AC: 22433 AN: 1403156 Hom.: 774 Cov.: 25 AF XY: 0.0173 AC XY: 12047 AN XY: 697346

African (AFR) AF: 0.143 AC: 4616 AN: 32368

American (AMR) AF: 0.0161 AC: 683 AN: 42492

Ashkenazi Jewish (ASJ) AF: 0.0116 AC: 282 AN: 24276

East Asian (EAS) AF: 0.00204 AC: 80 AN: 39234

South Asian (SAS) AF: 0.0729 AC: 6019 AN: 82530

European-Finnish (FIN) AF: 0.00172 AC: 89 AN: 51784

Middle Eastern (MID) AF: 0.0251 AC: 110 AN: 4384

European-Non Finnish (NFE) AF: 0.00853 AC: 9113 AN: 1067974

Other (OTH) AF: 0.0248 AC: 1441 AN: 58114

GnomAD4 genome AF: 0.0478 AC: 7268 AN: 152164 Hom.: 430 Cov.: 32 AF XY: 0.0470 AC XY: 3496 AN XY: 74404

African (AFR) AF: 0.135 AC: 5591 AN: 41464

American (AMR) AF: 0.0259 AC: 396 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3470

East Asian (EAS) AF: 0.00542 AC: 28 AN: 5168

South Asian (SAS) AF: 0.0863 AC: 416 AN: 4820

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10620

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.00871 AC: 592 AN: 68004

Other (OTH) AF: 0.0536 AC: 113 AN: 2110

Alfa AF: 0.0302 Hom.: 28

Bravo AF: 0.0533

Asia WGS AF: 0.0860 AC: 300 AN: 3478

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
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs142247529; hg19: chr21-47610939;