21-46228456-G-C

Variant names:

• chr21-46228456-G-C
• rs373275028
• NM_002340.6:c.158C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002340.6(LSS):​c.158C>G​(p.Ala53Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. A53V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LSS NM_002340.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.82
• 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]

MCM3AP-AS1 (HGNC:16417): (MCM3AP antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2562406).

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.158C>G	p.Ala53Gly	missense	Exon 2 of 22	NP_002331.3
	LSS	NM_001001438.3		c.158C>G	p.Ala53Gly	missense	Exon 2 of 23	NP_001001438.1	P48449-1
	LSS	NM_001145436.2		c.158C>G	p.Ala53Gly	missense	Exon 2 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.158C>G	p.Ala53Gly	missense	Exon 2 of 22	ENSP00000380837.2	P48449-1
	LSS	ENST00000356396.8	TSL:1	c.158C>G	p.Ala53Gly	missense	Exon 2 of 23	ENSP00000348762.3	P48449-1
	LSS	ENST00000457828.6	TSL:1	c.-83C>G		5_prime_UTR	Exon 1 of 21	ENSP00000409191.2	P48449-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000435 AC: 1 AN: 229668 AF XY: 0.00000787

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451174 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 722376

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111586

Other (OTH) AF: 0.00 AC: 0 AN: 60280

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000833 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.030
Eigen_PC	Benign	0.060
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		4.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.095
Sift	Uncertain	0.016	D
Sift4G	Benign	0.28	T
Polyphen		0.67	P
Vest4		0.34
MutPred		0.48		Loss of stability (P = 0.0596)
MVP		0.52
MPC		0.29
ClinPred		0.91	D
GERP RS		4.8
PromoterAI		0.0072	Neutral
Varity_R		0.51
gMVP		0.47
Mutation Taster		=57/43	polymorphism

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: rs373275028; hg19: chr21-47648370;