rs1192824648
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000271.5(NPC1):āc.1156A>Gā(p.Ser386Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,870 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 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.1156A>G | p.Ser386Gly | missense_variant | 8/25 | ENST00000269228.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.1156A>G | p.Ser386Gly | missense_variant | 8/25 | 1 | NM_000271.5 | P1 | |
NPC1 | ENST00000591051.1 | c.439A>G | p.Ser147Gly | missense_variant | 3/18 | 2 | |||
NPC1 | ENST00000540608.5 | n.1070A>G | non_coding_transcript_exon_variant | 6/16 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251252Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135804
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461870Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727238
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C1 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 25, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 04, 2023 | This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 386 of the NPC1 protein (p.Ser386Gly). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with Niemann-Pick type C (PMID: 27528516). ClinVar contains an entry for this variant (Variation ID: 553470). 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 with a positive predictive value of 95%. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at