rs753714824

Variant names:

• chr21-46228743-C-G
• rs753714824
• NM_002340.6:c.3G>C

Your query was ambiguous. Multiple possible variants found:

• chr21-46228743-C-G
• chr21-46228743-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate 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
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 81 codons. Genomic position: 46227630. Lost 0.110 part of the original CDS.
• 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 VariationId is 2861309.Status of the report is criteria_provided_single_submitter, 1 stars.

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.3G>C	p.Met1?	start_lost	Exon 1 of 22	NP_002331.3
	LSS	NM_001001438.3		c.3G>C	p.Met1?	start_lost	Exon 1 of 23	NP_001001438.1	P48449-1
	LSS	NM_001145436.2		c.3G>C	p.Met1?	start_lost	Exon 1 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.3G>C	p.Met1?	start_lost	Exon 1 of 22	ENSP00000380837.2	P48449-1
	LSS	ENST00000356396.8	TSL:1	c.3G>C	p.Met1?	start_lost	Exon 1 of 23	ENSP00000348762.3	P48449-1
	LSS	ENST00000457828.6	TSL:1	c.-370G>C		5_prime_UTR	Exon 1 of 21	ENSP00000409191.2	P48449-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.020	N
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-1.0	T
PhyloP100		1.2
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.15
Sift	Uncertain	0.018	D
Sift4G	Benign	0.19	T
Polyphen		0.043	B
Vest4		0.75
MutPred		1.0		Loss of MoRF binding (P = 0.0735)
MVP		0.25
ClinPred		0.96	D
GERP RS		1.9
PromoterAI		-0.28	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.77
gMVP		0.65
Mutation Taster		=34/166	disease causing

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

Other links and lift over

dbSNP: rs753714824; hg19: chr21-47648657;