chr21-46228743-C-G

Position:

• chr21-46228743-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_002340.6(LSS):​c.3G>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LSS NM_002340.6 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.23

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-46228743-C-G is Pathogenic according to our data. Variant chr21-46228743-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 2861309.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LSS	NM_002340.6	c.3G>C	p.Met1?	start_lost	1/22	ENST00000397728.8	NP_002331.3
LSS	NM_001001438.3	c.3G>C	p.Met1?	start_lost	1/23		NP_001001438.1
LSS	NM_001145436.2	c.3G>C	p.Met1?	start_lost	1/22		NP_001138908.1
LSS	NM_001145437.2	c.-370G>C		5_prime_UTR_variant	1/21		NP_001138909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LSS	ENST00000397728.8	c.3G>C	p.Met1?	start_lost	1/22	1	NM_002340.6	ENSP00000380837.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 24, 2023

This sequence change affects the initiator methionine of the LSS mRNA. The next in-frame methionine is located at codon 81. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with clinical features of LSS-related disorders (PMID: 35413293; Invitae). It has also been observed to segregate with disease in related individuals. Studies have shown that disruption of the initiator codon alters LSS gene expression (PMID: 35413293). This variant disrupts a region of the LSS protein in which other variant(s) (p.Tyr14Cys) have been observed in individuals with LSS-related conditions (PMID: 30723320). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.091	T;T;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.020	N
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	-0.87	N;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.018	D;D;D
Sift4G	Benign	0.19	T;T;T
Polyphen		0.043	B;B;.
Vest4		0.75
MutPred		1.0		Loss of MoRF binding (P = 0.0735);Loss of MoRF binding (P = 0.0735);Loss of MoRF binding (P = 0.0735);
MVP		0.25
ClinPred		0.96	D
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.77
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-47648657;