rs145362908
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBS1_SupportingBS2
The NM_000271.5(NPC1):c.2428G>T(p.Val810Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000437 in 1,614,192 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V810I) has been classified as Likely benign.
Frequency
Consequence
NM_000271.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.2428G>T | p.Val810Phe | missense_variant | 16/25 | ENST00000269228.10 | NP_000262.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.2428G>T | p.Val810Phe | missense_variant | 16/25 | 1 | NM_000271.5 | ENSP00000269228.4 | ||
NPC1 | ENST00000591051.1 | c.1504G>T | p.Val502Phe | missense_variant | 9/18 | 2 | ENSP00000467636.1 | |||
NPC1 | ENST00000540608.5 | n.2342G>T | non_coding_transcript_exon_variant | 14/16 | 2 | |||||
NPC1 | ENST00000586718.1 | n.219G>T | non_coding_transcript_exon_variant | 1/3 | 3 |
Frequencies
GnomAD3 genomes AF: 0.000414 AC: 63AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000541 AC: 136AN: 251482Hom.: 0 AF XY: 0.000515 AC XY: 70AN XY: 135912
GnomAD4 exome AF: 0.000439 AC: 642AN: 1461878Hom.: 2 Cov.: 32 AF XY: 0.000437 AC XY: 318AN XY: 727240
GnomAD4 genome AF: 0.000414 AC: 63AN: 152314Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28AN XY: 74480
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C1 Uncertain:3Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 11, 2018 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 29, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2020 | - - |
NPC1-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 10, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at