21-46228665-AGTCGCGCTCTCCTCAGCACCTAGGACCACCCCGCATTCGTCAGGAGCCCGGGGCGAGGGGACTCACGTGCCCTCCGTCATTGCTGCTGCAGTGCTCTACGCCGCCCACTGCCAGCTGCCAGATGTCCGCACCCGGGACCTGCCGCCCAGCCCCGCCCCTCCCGCCCCTCCCGCCCCTCCCGCCCCTCCCGCGCGCACTACGCAGGCGCAGGCCTCGGCAGGCGCTCAGGCTTAGGTGGGCCGACGCCCACGCAACCAATCAGAGCGCCGCGAGCGTGACCCCGGGGTGTGCCAGGCGACCACAGTGGTGGAGCGCTTGGTGCCCCATGCGGCGTGGGGC-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.451
Variant links:
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]

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ACMG classification

Classification made for transcript

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
LSSNM_002340.6 linkc.-259_14+66del exon_loss_variant, splice_region_variant 1/22 ENST00000397728.8 NP_002331.3
LSSNM_002340.6 linkc.-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
LSSNM_002340.6 linkc.-259_14+66del upstream_gene_variant ENST00000397728.8 NP_002331.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LSSENST00000397728.8 linkc.-259_14+66del exon_loss_variant, splice_region_variant 1/221 NM_002340.6 ENSP00000380837.2 P48449-1
LSSENST00000397728.8 linkc.-259_14+66del splice_donor_variant, 5_prime_UTR_truncation, exon_loss_variant, splice_region_variant, intron_variant 1/221 NM_002340.6 ENSP00000380837.2 P48449-1
LSSENST00000397728.8 linkc.-259_14+66del upstream_gene_variant 1 NM_002340.6 ENSP00000380837.2 P48449-1

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
LINK: link

Submissions by phenotype

Alopecia-intellectual disability syndrome 4 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingEquipe Genetique des Anomalies du Developpement, Université de Bourgogne-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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; API