chr18-23554875-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000271.5(NPC1):c.1436G>A(p.Cys479Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,170 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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.1436G>A | p.Cys479Tyr | missense_variant | Exon 9 of 25 | ENST00000269228.10 | NP_000262.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.1436G>A | p.Cys479Tyr | missense_variant | Exon 9 of 25 | 1 | NM_000271.5 | ENSP00000269228.4 | ||
NPC1 | ENST00000591051.1 | c.716G>A | p.Cys239Tyr | missense_variant | Exon 4 of 18 | 2 | ENSP00000467636.1 | |||
NPC1 | ENST00000540608.5 | n.1350G>A | non_coding_transcript_exon_variant | Exon 7 of 16 | 2 | |||||
NPC1 | ENST00000590301.1 | n.111G>A | non_coding_transcript_exon_variant | Exon 1 of 2 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152170Hom.: 0 Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461776Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727194
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152170Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74336
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C1 Pathogenic:2Uncertain:2
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 479 of the NPC1 protein (p.Cys479Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 16098014, 20718790; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 539310). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NPC1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
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The NPC1 c.1436G>A (p.Cys479Tyr) missense variant has been reported in two studies and is found in two individuals with Niemann-Pick disease type C, including one each in a compound heterozygous state with a second missense variant and in a heterozygous state (Fernandez-Valero et al. 2005; Macias-Vidal et al. 2011). The p.Cys479Tyr variant was absent from 100 controls and is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium or the Genome Aggregation Database. Based on the limited evidence, the p.Cys479Tyr variant is classified as a variant of unknown significance but suspicious for pathogenicity for Niemann-Pick disease type C. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Inborn genetic diseases Pathogenic:1
The c.1436G>A (p.C479Y) alteration is located in coding exon 9 of the NPC1 gene. This alteration results from a G to A substitution at nucleotide position 1436, causing the cysteine (C) at amino acid position 479 to be replaced by a tyrosine (Y). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in a Spanish child who developed generalized seizures at age 9 and was later diagnosed with Niemann-Pick disease type C at age 11. The child was heterozygous for this variant and a second mutation was not able to be detected (Fernandez-Valero 2005; Macías-Vidal 2011). This variant was also reported in trans with a second NPC1 mutation (p.A1054T c.3160G>A) in another Spanish child with severe infantile onset (Macías-Vidal 2011). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -
not provided Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at