rs770321568
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3_ModeratePP5
The NM_000271.5(NPC1):c.1947+5G>C variant causes a splice donor 5th base, intron change. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 29)
Exomes 𝑓: 0.0000053 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
NPC1
NM_000271.5 splice_donor_5th_base, intron
NM_000271.5 splice_donor_5th_base, intron
Scores
2
Splicing: ADA: 0.9998
2
Clinical Significance
Conservation
PhyloP100: 5.79
Genes affected
NPC1 (HGNC:7897): (NPC intracellular cholesterol transporter 1) This gene encodes a large protein that resides in the limiting membrane of endosomes and lysosomes and mediates intracellular cholesterol trafficking via binding of cholesterol to its N-terminal domain. It is predicted to have a cytoplasmic C-terminus, 13 transmembrane domains, and 3 large loops in the lumen of the endosome - the last loop being at the N-terminus. This protein transports low-density lipoproteins to late endosomal/lysosomal compartments where they are hydrolized and released as free cholesterol. Defects in this gene cause Niemann-Pick type C disease, a rare autosomal recessive neurodegenerative disorder characterized by over accumulation of cholesterol and glycosphingolipids in late endosomal/lysosomal compartments.[provided by RefSeq, Aug 2009]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 18-23544955-C-G is Pathogenic according to our data. Variant chr18-23544955-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281945.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Likely_pathogenic=2, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.1947+5G>C | splice_donor_5th_base_variant, intron_variant | ENST00000269228.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.1947+5G>C | splice_donor_5th_base_variant, intron_variant | 1 | NM_000271.5 | P1 | |||
NPC1 | ENST00000591051.1 | c.1025+5G>C | splice_donor_5th_base_variant, intron_variant | 2 | |||||
NPC1 | ENST00000540608.5 | n.1861+5G>C | splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 29
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GnomAD3 exomes AF: 0.00000801 AC: 2AN: 249836Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135240
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000531 AC: 7AN: 1319098Hom.: 0 Cov.: 27 AF XY: 0.00000604 AC XY: 4AN XY: 661904
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GnomAD4 genome ? Cov.: 29
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Niemann-Pick disease, type C1 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 31, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 04, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the NPC1 protein in which other variant(s) (p.Gly640Arg) have been determined to be pathogenic (PMID: 12955717, 27581084). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in the activation of a cryptic splice site in exon 12 (PMID: 28328115). Studies have shown that this variant alters NPC1 gene expression (PMID: 30202070). ClinVar contains an entry for this variant (Variation ID: 281945). This variant has been observed in individual(s) with Niemann-Pick Type C (PMID: 28328115). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change falls in intron 12 of the NPC1 gene. It does not directly change the encoded amino acid sequence of the NPC1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 25 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. - |
Niemann-Pick disease, type C Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 30, 2022 | Variant summary: NPC1 c.1947+5G>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predicts the variant abolishes a 5' splicing donor site and three predict the variant weakens a 5' donor site. Experimental evidence supports these predictions indicating the variant affects mRNA splicing (Salman_2017). The variant allele was found at a frequency of 8e-06 in 249836 control chromosomes (gnomAD). c.1947+5G>C has been reported in the literature in individuals affected with Niemann-Pick Disease (e.g. Mazzacuva_2016, Salman_2017, Schultz_2018). These data indicate that the variant may be associated with disease. Three ClinVar submitters have assessed the variant since 2014: one classified the variant as of uncertain significance, and two as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 20, 2018 | - - |
NPC1-related condition Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 25, 2023 | The NPC1 c.1947+5G>C variant is predicted to interfere with splicing. This variant has been reported in individuals with Niemann-Pick disease, type C (Salman et al. 2017. PubMed ID: 28328115; Table S1, Mazzacuva et al. 2016. PubMed ID: 27139891). In vitro functional studies demonstrate this variant affects splicing as well as has an effect on NPC1 function (Figure 1C and D, Salman et al 2017. PubMed ID: 28328115; Figure 1D, Schultz et al. 2018. PubMed ID: 30202070 ). This variant is reported in 0.0018% of alleles in individuals of European (non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-21124919-C-G). This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
Name
Calibrated prediction
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at