rs80358251
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM5BP4_StrongBP6BS1BS2
The NM_000271.5(NPC1):c.709C>T(p.Pro237Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,614,168 control chromosomes in the GnomAD database, including 195 homozygotes. In-silico tool predicts 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. P237L) has been classified as Pathogenic.
Frequency
Consequence
NM_000271.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.709C>T | p.Pro237Ser | missense_variant | 6/25 | ENST00000269228.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.709C>T | p.Pro237Ser | missense_variant | 6/25 | 1 | NM_000271.5 | P1 | |
NPC1 | ENST00000540608.5 | n.623C>T | non_coding_transcript_exon_variant | 4/16 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0101 AC: 1530AN: 152226Hom.: 17 Cov.: 32
GnomAD3 exomes AF: 0.00988 AC: 2478AN: 250694Hom.: 26 AF XY: 0.00961 AC XY: 1302AN XY: 135546
GnomAD4 exome AF: 0.0138 AC: 20169AN: 1461824Hom.: 178 Cov.: 32 AF XY: 0.0133 AC XY: 9695AN XY: 727222
GnomAD4 genome ? AF: 0.0100 AC: 1528AN: 152344Hom.: 17 Cov.: 32 AF XY: 0.00966 AC XY: 720AN XY: 74510
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C1 Uncertain:1Benign:5Other:1
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | Sep 07, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Benign, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | May 31, 2018 | This variant is interpreted as a Benign, for Niemann-Pick disease, type C1, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (PMID:12554680). BS1 => Allele frequency is greater than expected for disorder (PMID:11182931). BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. - |
Likely benign, criteria provided, single submitter | literature only | Counsyl | Aug 22, 2014 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
not specified Benign:5
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 24, 2015 | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
not provided Benign:3
Likely benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 21, 2018 | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | This variant is associated with the following publications: (PMID: 32222928, 29631617, 28328115, 25842391, 10480349, 20981092, 12955717, 12554680, 22995991, 25497598, 20489167) - |
Nasopharyngeal carcinoma Benign:1
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 11, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at