rs752896980
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000271.5(NPC1):c.7G>A(p.Ala3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000179 in 1,533,936 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A3V) has been classified as Uncertain significance.
Frequency
Consequence
NM_000271.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.7G>A | p.Ala3Thr | missense_variant | 1/25 | ENST00000269228.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.7G>A | p.Ala3Thr | missense_variant | 1/25 | 1 | NM_000271.5 | P1 | |
NPC1 | ENST00000540608.5 | n.151G>A | non_coding_transcript_exon_variant | 1/16 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000788 AC: 12AN: 152234Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000232 AC: 3AN: 129560Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 71018
GnomAD4 exome AF: 0.000190 AC: 262AN: 1381584Hom.: 0 Cov.: 31 AF XY: 0.000194 AC XY: 132AN XY: 681900
GnomAD4 genome AF: 0.0000788 AC: 12AN: 152352Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8AN XY: 74508
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C1 Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 14, 2022 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 03, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 05, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 03, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 3 of the NPC1 protein (p.Ala3Thr). This variant is present in population databases (rs752896980, gnomAD 0.008%). This missense change has been observed in individual(s) with Niemann-Pick Type C (PMID: 32931663). ClinVar contains an entry for this variant (Variation ID: 555997). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 22, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at