21-46228665-AGTCGCGCTCTCCTCAGCACCTAGGACCACCCCGCATTCGTCAGGAGCCCGGGGCGAGGGGACTCACGTGCCCTCCGTCATTGCTGCTGCAGTGCTCTACGCCGCCCACTGCCAGCTGCCAGATGTCCGCACCCGGGACCTGCCGCCCAGCCCCGCCCCTCCCGCCCCTCCCGCCCCTCCCGCCCCTCCCGCGCGCACTACGCAGGCGCAGGCCTCGGCAGGCGCTCAGGCTTAGGTGGGCCGACGCCCACGCAACCAATCAGAGCGCCGCGAGCGTGACCCCGGGGTGTGCCAGGCGACCACAGTGGTGGAGCGCTTGGTGCCCCATGCGGCGTGGGGC-A

Position:

• chr21-46228665-AGTCGCGCTCTCCTCAGCACCTAGGACCACCCCGCATTCGTCAGGAGCCCGGGGCGAGGGGACTCACGTGCCCTCCGTCATTGCTGCTGCAGTGCTCTACGCCGCCCACTGCCAGCTGCCAGATGTCCGCACCCGGGACCTGCCGCCCAGCCCCGCCCCTCCCGCCCCTCCCGCCCCTCCCGCCCCTCCCGCGCGCACTACGCAGGCGCAGGCCTCGGCAGGCGCTCAGGCTTAGGTGGGCCGACGCCCACGCAACCAATCAGAGCGCCGCGAGCGTGACCCCGGGGTGTGCCAGGCGACCACAGTGGTGGAGCGCTTGGTGCCCCATGCGGCGTGGGGC-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_002340.6(LSS):​c.-259_14+66del variant causes a exon loss, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LSS NM_002340.6 exon_loss, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.451

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-46228665-AGTCGCGCTCTCCTCAGCACCTAGGACCACCCCGCATTCGTCAGGAGCCCGGGGCGAGGGGACTCACGTGCCCTCCGTCATTGCTGCTGCAGTGCTCTACGCCGCCCACTGCCAGCTGCCAGATGTCCGCACCCGGGACCTGCCGCCCAGCCCCGCCCCTCCCGCCCCTCCCGCCCCTCCCGCCCCTCCCGCGCGCACTACGCAGGCGCAGGCCTCGGCAGGCGCTCAGGCTTAGGTGGGCCGACGCCCACGCAACCAATCAGAGCGCCGCGAGCGTGACCCCGGGGTGTGCCAGGCGACCACAGTGGTGGAGCGCTTGGTGCCCCATGCGGCGTGGGGC-A is Pathogenic according to our data. Variant chr21-46228665-AGTCGCGCTCTCCTCAGCACCTAGGACCACCCCGCATTCGTCAGGAGCCCGGGGCGAGGGGACTCACGTGCCCTCCGTCATTGCTGCTGCAGTGCTCTACGCCGCCCACTGCCAGCTGCCAGATGTCCGCACCCGGGACCTGCCGCCCAGCCCCGCCCCTCCCGCCCCTCCCGCCCCTCCCGCCCCTCCCGCGCGCACTACGCAGGCGCAGGCCTCGGCAGGCGCTCAGGCTTAGGTGGGCCGACGCCCACGCAACCAATCAGAGCGCCGCGAGCGTGACCCCGGGGTGTGCCAGGCGACCACAGTGGTGGAGCGCTTGGTGCCCCATGCGGCGTGGGGC-A is described in ClinVar as [Pathogenic]. Clinvar id is 1707554.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.-259_14+66del		exon_loss_variant, splice_region_variant	1/22	ENST00000397728.8	NP_002331.3
LSS	NM_002340.6	c.-259_14+66del		splice_donor_variant, 5_prime_UTR_truncation, exon_loss_variant, splice_region_variant, intron_variant	1/22	ENST00000397728.8	NP_002331.3
LSS	NM_002340.6	c.-259_14+66del		upstream_gene_variant		ENST00000397728.8	NP_002331.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LSS	ENST00000397728.8	c.-259_14+66del		exon_loss_variant, splice_region_variant	1/22	1	NM_002340.6	ENSP00000380837.2
LSS	ENST00000397728.8	c.-259_14+66del		splice_donor_variant, 5_prime_UTR_truncation, exon_loss_variant, splice_region_variant, intron_variant	1/22	1	NM_002340.6	ENSP00000380837.2
LSS	ENST00000397728.8	c.-259_14+66del		upstream_gene_variant		1	NM_002340.6	ENSP00000380837.2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Alopecia-intellectual disability syndrome 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

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Computational scores

Source: dbNSFP v4.3

Splicing

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: chr21-47648579;