21-46194555-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002340.6(LSS):c.1924T>A(p.Leu642Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L642V) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: LSS NM_002340.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.50

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10157344).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LSS	NM_002340.6	c.1924T>A	p.Leu642Met	missense_variant	20/22	ENST00000397728.8
LSS	NM_001001438.3	c.1924T>A	p.Leu642Met	missense_variant	20/23
LSS	NM_001145436.2	c.1891T>A	p.Leu631Met	missense_variant	20/22
LSS	NM_001145437.2	c.1684T>A	p.Leu562Met	missense_variant	19/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LSS	ENST00000397728.8	c.1924T>A	p.Leu642Met	missense_variant	20/22	1	NM_002340.6	P1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250214 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135438

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461388 Hom.: 0 Cov.: 58 AF XY: 0.00000413 AC XY: 3 AN XY: 727000

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 35

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	20
Dann	Benign	0.97
DEOGEN2	Benign	0.037	T;T;.;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.73	D
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.10	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.48	N;N;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.10	N;N;N;N
REVEL	Benign	0.032
Sift	Uncertain	0.023	D;D;D;D
Sift4G	Uncertain	0.029	D;D;D;D
Polyphen		0.018	B;B;.;.
Vest4		0.20
MutPred		0.35		Gain of disorder (P = 0.07);Gain of disorder (P = 0.07);.;.;
MVP		0.25
MPC		0.28
ClinPred		0.075	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2254524; hg19: chr21-47614469;