rs864622780

chr21-46195752-A-TchrNT_187626.1-57121-A-Tchr21-46195752-A-GchrNT_187626.1-57121-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1 PM1 PM2 PP3_Strong

The NM_002340.6(LSS):c.1741T>A(p.Trp581Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LSS NM_002340.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.84

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PS1: Transcript NM_002340.6 (LSS) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 221227
• PM1: In a site Transition state stabilizer (size 0) in uniprot entity LSS_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LSS	NM_002340.6	c.1741T>A	p.Trp581Arg	missense_variant	19/22	ENST00000397728.8
LSS	NM_001001438.3	c.1741T>A	p.Trp581Arg	missense_variant	19/23
LSS	NM_001145436.2	c.1708T>A	p.Trp570Arg	missense_variant	19/22
LSS	NM_001145437.2	c.1501T>A	p.Trp501Arg	missense_variant	18/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LSS	ENST00000397728.8	c.1741T>A	p.Trp581Arg	missense_variant	19/22	1	NM_002340.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Pathogenic	4.6	H;H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-14	D;D;D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.010	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.99
MutPred		0.92		Gain of disorder (P = 0.0289);Gain of disorder (P = 0.0289);.;.;
MVP		0.81
MPC		1.3
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.95
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs864622780; hg19: chr21-47615666;