chr21-46191371-T-C

Variant names:

• chr21-46191371-T-C
• rs73144744
• NM_002340.6:c.2068-136A>G

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.2068-136A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 917,238 control chromosomes in the GnomAD database, including 7,933 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1407 hom., cov: 33)
  • Exomes 𝑓: 0.12 (6526 hom.)
• Consequence: LSS NM_002340.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.21
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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=-0.9).
• BP6: Variant 21-46191371-T-C is Benign according to our data. Variant chr21-46191371-T-C is described in ClinVar as Benign. ClinVar VariationId is 1277484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.152 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.2068-136A>G		intron	N/A	NP_002331.3
	LSS	NM_001001438.3		c.2068-136A>G		intron	N/A	NP_001001438.1	P48449-1
	LSS	NM_001145436.2		c.2035-136A>G		intron	N/A	NP_001138908.1	P48449-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LSS	ENST00000397728.8	TSL:1 MANE Select	c.2068-136A>G		intron	N/A	ENSP00000380837.2	P48449-1
	LSS	ENST00000356396.8	TSL:1	c.2068-136A>G		intron	N/A	ENSP00000348762.3	P48449-1
	LSS	ENST00000457828.6	TSL:1	c.1828-136A>G		intron	N/A	ENSP00000409191.2	P48449-2

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19365 AN: 152070 Hom.: 1409 Cov.: 33

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.0984

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0547

Gnomad FIN AF: 0.0563

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.153

GnomAD4 exome AF: 0.119 AC: 91314 AN: 765050 Hom.: 6526 AF XY: 0.118 AC XY: 46860 AN XY: 395956

African (AFR) AF: 0.153 AC: 3002 AN: 19570

American (AMR) AF: 0.0785 AC: 2579 AN: 32854

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 3610 AN: 17450

East Asian (EAS) AF: 0.000251 AC: 9 AN: 35900

South Asian (SAS) AF: 0.0627 AC: 3834 AN: 61142

European-Finnish (FIN) AF: 0.0602 AC: 2356 AN: 39120

Middle Eastern (MID) AF: 0.198 AC: 690 AN: 3488

European-Non Finnish (NFE) AF: 0.136 AC: 70639 AN: 518828

Other (OTH) AF: 0.125 AC: 4595 AN: 36698

GnomAD4 genome AF: 0.127 AC: 19373 AN: 152188 Hom.: 1407 Cov.: 33 AF XY: 0.120 AC XY: 8966 AN XY: 74412

African (AFR) AF: 0.156 AC: 6454 AN: 41492

American (AMR) AF: 0.0983 AC: 1504 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 715 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5174

South Asian (SAS) AF: 0.0552 AC: 266 AN: 4822

European-Finnish (FIN) AF: 0.0563 AC: 597 AN: 10610

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.138 AC: 9356 AN: 67996

Other (OTH) AF: 0.151 AC: 319 AN: 2116

Alfa AF: 0.125 Hom.: 172

Bravo AF: 0.135

Asia WGS AF: 0.0470 AC: 167 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: 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	-0.90
CADD	Benign	0.55
DANN	Benign	0.22
PhyloP100		-1.2
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: rs73144744; hg19: chr21-47611285;