chr18-23535683-T-C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The NM_000271.5(NPC1):āc.3263A>Gā(p.Tyr1088Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,386 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 Pathogenic (ā ). Synonymous variant affecting the same amino acid position (i.e. Y1088Y) has been classified as Likely benign.
Frequency
Consequence
NM_000271.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.3263A>G | p.Tyr1088Cys | missense_variant | 22/25 | ENST00000269228.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.3263A>G | p.Tyr1088Cys | missense_variant | 22/25 | 1 | NM_000271.5 | P1 | |
NPC1 | ENST00000591051.1 | c.2342A>G | p.Tyr781Cys | missense_variant | 15/18 | 2 | |||
NPC1 | ENST00000586150.5 | c.20A>G | p.Tyr7Cys | missense_variant | 1/4 | 3 | |||
NPC1 | ENST00000588867.1 | n.18A>G | non_coding_transcript_exon_variant | 1/3 | 5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461386Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727056
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C1, juvenile form Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 1999 | - - |
Niemann-Pick disease, type C1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 23, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NPC1 function (PMID: 31699992). 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. ClinVar contains an entry for this variant (Variation ID: 2964). This missense change has been observed in individuals with NPC1-related conditions (PMID: 10480349, 23711246, 26666848). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1088 of the NPC1 protein (p.Tyr1088Cys). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at