chr18-23539465-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000271.5(NPC1):c.2801G>A(p.Arg934Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,610,568 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R934L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000271.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.2801G>A | p.Arg934Gln | missense_variant | 19/25 | ENST00000269228.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.2801G>A | p.Arg934Gln | missense_variant | 19/25 | 1 | NM_000271.5 | P1 | |
NPC1 | ENST00000591051.1 | c.1880G>A | p.Arg627Gln | missense_variant | 12/18 | 2 | |||
NPC1 | ENST00000591075.1 | n.434G>A | non_coding_transcript_exon_variant | 1/3 | 4 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152154Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248664Hom.: 0 AF XY: 0.00000745 AC XY: 1AN XY: 134228
GnomAD4 exome AF: 0.0000158 AC: 23AN: 1458414Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 725488
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152154Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74326
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C1 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jan 06, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Feb 18, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 04, 2020 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in several individuals affected with Niemann-Pick disease (PMID: 10521290, 16126423, 17160617, 25236789). ClinVar contains an entry for this variant (Variation ID: 189117). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 934 of the NPC1 protein (p.Arg934Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at