rs1190383931
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000271.5(NPC1):āc.1526A>Cā(p.Tyr509Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 33)
Exomes š: 0.0000082 ( 0 hom. )
Consequence
NPC1
NM_000271.5 missense
NM_000271.5 missense
Scores
10
8
1
Clinical Significance
Conservation
PhyloP100: 3.88
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 Likely_pathogenic. Variant got 9 ACMG points.
PM1
In a topological_domain Lumenal (size 248) in uniprot entity NPC1_HUMAN there are 30 pathogenic changes around while only 10 benign (75%) in NM_000271.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.982
PP5
Variant 18-23554785-T-G is Pathogenic according to our data. Variant chr18-23554785-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 554002.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.1526A>C | p.Tyr509Ser | missense_variant | 9/25 | ENST00000269228.10 | NP_000262.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.1526A>C | p.Tyr509Ser | missense_variant | 9/25 | 1 | NM_000271.5 | ENSP00000269228.4 | ||
NPC1 | ENST00000591051.1 | c.806A>C | p.Tyr269Ser | missense_variant | 4/18 | 2 | ENSP00000467636.1 | |||
NPC1 | ENST00000540608.5 | n.1440A>C | non_coding_transcript_exon_variant | 7/16 | 2 | |||||
NPC1 | ENST00000590301.1 | n.201A>C | non_coding_transcript_exon_variant | 1/2 | 2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461776Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727204
GnomAD4 exome
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1461776
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GnomAD4 genome Cov.: 33
GnomAD4 genome
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33
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
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 | Sep 22, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 04, 2023 | This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr509 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been observed in individuals with NPC1-related conditions (PMID: 22676771), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NPC1 protein function. ClinVar contains an entry for this variant (Variation ID: 554002). This missense change has been observed in individuals with Niemann-Pick disease type C (PMID: 26666848, 30202070; Invitae). It has also been observed to segregate with disease in related individuals. This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 509 of the NPC1 protein (p.Tyr509Ser). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 06, 2024 | Variant summary: NPC1 c.1526A>C (p.Tyr509Ser) results in a non-conservative amino acid change located in the NPC1, middle luminal domain (IPR053956) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251406 control chromosomes. c.1526A>C has been reported in the literature in the heterozygous (2nd allele not specified), presumed compound heterozygous, and compound heterozygous state in multiple individuals affected with Niemann-Pick Disease Type C (example, Garver_2010, Imrie_2015, Park_2003). These data indicate that the variant may be associated with disease. Three publications report experimental evidence evaluating an impact on protein function in a human fibroblast cell line carrying a 2nd pathogenic allele in trans, however the impact of this variant alone could not be determined (example, Pepponi_2022, Schultz_2018, Yu_2012). The following publications have been ascertained in the context of this evaluation (PMID: 19744920, 26666848, 12955717, 35408815, 30202070, 22505584). ClinVar contains an entry for this variant (Variation ID: 554002). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MutPred
Loss of sheet (P = 0.0315);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at