NM_002340.6:c.*33G>A

Variant names:

• chr21-46191071-C-T
• rs78413826
• NM_002340.6:c.*33G>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.*33G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00611 in 1,612,978 control chromosomes in the GnomAD database, including 419 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (27 hom., cov: 33)
  • Exomes 𝑓: 0.0062 (392 hom.)
• Consequence: LSS NM_002340.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.440
• Publications: 1 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=-0.83).
• BP6: Variant 21-46191071-C-T is Benign according to our data. Variant chr21-46191071-C-T is described in ClinVar as Benign. ClinVar VariationId is 1235234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0727 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.*33G>A		3_prime_UTR	Exon 22 of 22	NP_002331.3
	LSS	NM_001001438.3		c.*33G>A		3_prime_UTR	Exon 22 of 23	NP_001001438.1	P48449-1
	LSS	NM_001145436.2		c.*33G>A		3_prime_UTR	Exon 22 of 22	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.*33G>A		3_prime_UTR	Exon 22 of 22	ENSP00000380837.2	P48449-1
	LSS	ENST00000356396.8	TSL:1	c.*33G>A		3_prime_UTR	Exon 22 of 23	ENSP00000348762.3	P48449-1
	LSS	ENST00000457828.6	TSL:1	c.*33G>A		3_prime_UTR	Exon 21 of 21	ENSP00000409191.2	P48449-2

Frequencies

GnomAD3 genomes AF: 0.00476 AC: 725 AN: 152158 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00868

Gnomad SAS AF: 0.0792

Gnomad FIN AF: 0.0214

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.0130 AC: 3211 AN: 247566 AF XY: 0.0164

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.00648

Gnomad FIN exome AF: 0.0178

Gnomad NFE exome AF: 0.000643

Gnomad OTH exome AF: 0.00756

GnomAD4 exome AF: 0.00624 AC: 9119 AN: 1460702 Hom.: 392 Cov.: 31 AF XY: 0.00848 AC XY: 6165 AN XY: 726588

African (AFR) AF: 0.00123 AC: 41 AN: 33468

American (AMR) AF: 0.000358 AC: 16 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0000768 AC: 2 AN: 26054

East Asian (EAS) AF: 0.0116 AC: 461 AN: 39676

South Asian (SAS) AF: 0.0810 AC: 6985 AN: 86182

European-Finnish (FIN) AF: 0.0175 AC: 933 AN: 53246

Middle Eastern (MID) AF: 0.00270 AC: 15 AN: 5556

European-Non Finnish (NFE) AF: 0.000210 AC: 233 AN: 1111546

Other (OTH) AF: 0.00718 AC: 433 AN: 60298

GnomAD4 genome AF: 0.00480 AC: 731 AN: 152276 Hom.: 27 Cov.: 33 AF XY: 0.00713 AC XY: 531 AN XY: 74456

African (AFR) AF: 0.00108 AC: 45 AN: 41546

American (AMR) AF: 0.000327 AC: 5 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00870 AC: 45 AN: 5174

South Asian (SAS) AF: 0.0792 AC: 382 AN: 4822

European-Finnish (FIN) AF: 0.0214 AC: 227 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68030

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00110 Hom.: 0

Bravo AF: 0.00127

Asia WGS AF: 0.0480 AC: 168 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	-0.83
CADD	Benign	12
DANN	Benign	0.46
PhyloP100		0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
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: rs78413826; hg19: chr21-47610985;