rs1181604094
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000271.5(NPC1):āc.2597T>Cā(p.Met866Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,740 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 Uncertain significance (ā ā ).
Frequency
Consequence
NM_000271.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.2597T>C | p.Met866Thr | missense_variant | Exon 17 of 25 | ENST00000269228.10 | NP_000262.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.2597T>C | p.Met866Thr | missense_variant | Exon 17 of 25 | 1 | NM_000271.5 | ENSP00000269228.4 | ||
NPC1 | ENST00000591051.1 | c.1673T>C | p.Met558Thr | missense_variant | Exon 10 of 18 | 2 | ENSP00000467636.1 | |||
NPC1 | ENST00000540608.5 | n.2511T>C | non_coding_transcript_exon_variant | Exon 15 of 16 | 2 | |||||
NPC1 | ENST00000586718.1 | n.388T>C | non_coding_transcript_exon_variant | Exon 2 of 3 | 3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249142Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134688
GnomAD4 exome AF: 6.92e-7 AC: 1AN: 1444740Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 719526
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C1 Uncertain:2
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.85; 3Cnet: 0.92). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with NPC1 related disorder (PMID: 26981555). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at