rs1428599096
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000271.5(NPC1):c.2833G>A(p.Asp945Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,568 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). Synonymous variant affecting the same amino acid position (i.e. D945D) has been classified as Likely benign.
Frequency
Consequence
NM_000271.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.2833G>A | p.Asp945Asn | missense_variant | 19/25 | ENST00000269228.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.2833G>A | p.Asp945Asn | missense_variant | 19/25 | 1 | NM_000271.5 | P1 | |
NPC1 | ENST00000591051.1 | c.1912G>A | p.Asp638Asn | missense_variant | 12/18 | 2 | |||
NPC1 | ENST00000591075.1 | n.466G>A | non_coding_transcript_exon_variant | 1/3 | 4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250474Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135286
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461364Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 726906
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74366
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 26, 2022 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 945 of the NPC1 protein (p.Asp945Asn). 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 missense change has been observed in individual(s) with Niemann-Pick disease type C for which no second variant in NPC1 was found (PMID: 12955717, 19744920). ClinVar contains an entry for this variant (Variation ID: 539312). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
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 | Dec 02, 2022 | Variant summary: NPC1 c.2833G>A (p.Asp945Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250474 control chromosomes (gnomAD). c.2833G>A has been reported in the literature in individuals affected with Niemann-Pick Disease Type C and was reported to cause 'severe' biochemical phenotype (Park_2003, Garver_2010, Ribas_2016, Lopez de Frutos_2021). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function, demonstrated the variant to cause a reduction in total protein expression and result in protein of distinct molecular weights, one equivalent to the wild type and the other equivalent to that found in lower-molecular-weight mutants. Furthermore, the variant showed defective cholesterol trafficking. Taken together, the authors concluded the variant to be pathogenic (Erwood_2019). Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at