rs111256741
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_000271.5(NPC1):c.547G>T(p.Ala183Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A183T) has been classified as Uncertain significance.
Frequency
Consequence
NM_000271.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.547G>T | p.Ala183Ser | missense_variant | 5/25 | ENST00000269228.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.547G>T | p.Ala183Ser | missense_variant | 5/25 | 1 | NM_000271.5 | P1 | |
NPC1 | ENST00000540608.5 | n.461G>T | non_coding_transcript_exon_variant | 3/16 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152176Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251474Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135910
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461828Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727220
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74334
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 15, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 183 of the NPC1 protein (p.Ala183Ser). This variant is present in population databases (rs111256741, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with NPC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1448382). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at