rs773767253
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_000271.5(NPC1):āc.2903A>Gā(p.Asn968Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,610,350 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
Consequence
NM_000271.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.2903A>G | p.Asn968Ser | missense_variant | 19/25 | ENST00000269228.10 | NP_000262.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.2903A>G | p.Asn968Ser | missense_variant | 19/25 | 1 | NM_000271.5 | ENSP00000269228 | P1 | |
NPC1 | ENST00000591051.1 | c.1982A>G | p.Asn661Ser | missense_variant | 12/18 | 2 | ENSP00000467636 | |||
NPC1 | ENST00000591075.1 | n.536A>G | non_coding_transcript_exon_variant | 1/3 | 4 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152208Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251036Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135642
GnomAD4 exome AF: 0.0000158 AC: 23AN: 1458142Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 725594
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152208Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74358
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C1 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 10, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 04, 2024 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 968 of the NPC1 protein (p.Asn968Ser). This variant is present in population databases (rs773767253, gnomAD 0.008%). This missense change has been observed in individual(s) with Niemann-Pick type C (PMID: 16126423, 26666848, 32138288). ClinVar contains an entry for this variant (Variation ID: 554989). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NPC1 protein function. For these reasons, this variant has been classified as Pathogenic. - |
Niemann-Pick disease, type C Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 25, 2022 | Variant summary: NPC1 c.2903A>G (p.Asn968Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251036 control chromosomes (gnomAD). c.2903A>G has been reported in the literature in multiple individuals affected with Niemann-Pick Disease Type C (e.g. Millat_2005, Yang_2005, Imrie_2015, Reunert_2016, Dardis_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at