chr18-23533363-CTGAG-C
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000271.5(NPC1):βc.3742_3745delβ(p.Leu1248ValfsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,613,708 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. L1248L) has been classified as Likely benign.
Frequency
Consequence
NM_000271.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.3742_3745del | p.Leu1248ValfsTer3 | frameshift_variant | 24/25 | ENST00000269228.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.3742_3745del | p.Leu1248ValfsTer3 | frameshift_variant | 24/25 | 1 | NM_000271.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152200Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251390Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135890
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461508Hom.: 0 AF XY: 0.0000206 AC XY: 15AN XY: 727082
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152200Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74340
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C1 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 14, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 02, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 27, 2023 | This sequence change creates a premature translational stop signal (p.Leu1248Valfs*3) in the NPC1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 31 amino acid(s) of the NPC1 protein. This variant is present in population databases (rs774943545, gnomAD 0.06%). This premature translational stop signal has been observed in individuals with Niemann-Pick type C (PMID: 10521290, 19744920). It has also been observed to segregate with disease in related individuals. This variant is also known as c.3741_3744delACTC. ClinVar contains an entry for this variant (Variation ID: 487441). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. - |
Niemann-Pick disease, type C Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 03, 2017 | Variant summary: The NPC1 c.3742_3745delCTCA (p.Leu1248Valfs) variant (also known as 3741_3744delACTC) results in a premature termination codon, predicted to cause a truncated or absent NPC1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 5/121194 control chromosomes from ExAC at a frequency of 0.0000413, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPC1 variant (0.0027735). The variant was detected in at least three patients with NPC. Variant downsteam of this variant c.3744_3747 delCAGT has also been reported in affected individual and listed as "DM-disease mutation" in HGMD, suggesitng this location is a mutation hotspot. Taken together, this variant is classified as pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 19, 2019 | Reported in a family with a patient with Niemann-Pick type II disease; however, additional clinical information and biochemical studies on the patient were not provided (Greer et al., 1999); Reported in two patients with Niemann-Pick type C1 disease who have second NPC1 variants; however, segregation information was not provided to establish phase of the variants; for one patient, variant was reported as c.3741_3744delACTC due to the use of alternative nomenclature (Garver et al., 2010); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 31 amino acids are lost and replaced with 2 incorrect amino acids; This variant is associated with the following publications: (PMID: 28193631, 19744920, 10521290, 28082351) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at