rs761910746
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000271.5(NPC1):c.2908_2909insTT(p.Ser970PhefsTer14) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S970S) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
NPC1
NM_000271.5 frameshift
NM_000271.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.13
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 Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 18-23539357-G-GAA is Pathogenic according to our data. Variant chr18-23539357-G-GAA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553623.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.2908_2909insTT | p.Ser970PhefsTer14 | frameshift_variant | 19/25 | ENST00000269228.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.2908_2909insTT | p.Ser970PhefsTer14 | frameshift_variant | 19/25 | 1 | NM_000271.5 | P1 | |
NPC1 | ENST00000591051.1 | c.1986_1987insTT | p.Ser663PhefsTer14 | frameshift_variant | 12/18 | 2 | |||
NPC1 | ENST00000591075.1 | n.541_542insTT | non_coding_transcript_exon_variant | 1/3 | 4 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250854Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135530
GnomAD3 exomes
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250854
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135530
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GnomAD4 exome Cov.: 31
GnomAD4 exome
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31
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Niemann-Pick disease, type C1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 14, 2017 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at