18-23532218-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_000271.5(NPC1):c.3821G>A(p.Arg1274Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1274W) has been classified as Uncertain significance.
Frequency
Consequence
NM_000271.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.3821G>A | p.Arg1274Gln | missense_variant | 25/25 | ENST00000269228.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.3821G>A | p.Arg1274Gln | missense_variant | 25/25 | 1 | NM_000271.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152128Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251482Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135918
GnomAD4 exome AF: 0.000150 AC: 220AN: 1461894Hom.: 0 Cov.: 31 AF XY: 0.000158 AC XY: 115AN XY: 727248
GnomAD4 genome AF: 0.0000592 AC: 9AN: 152128Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74312
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C1 Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 27, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1274 of the NPC1 protein (p.Arg1274Gln). This variant is present in population databases (rs151305963, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with NPC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 539311). 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 not 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, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at