rs34084984
Positions:
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2
The NM_000271.5(NPC1):āc.2882A>Gā(p.Asn961Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000607 in 1,613,762 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.0032 ( 4 hom., cov: 33)
Exomes š: 0.00033 ( 2 hom. )
Consequence
NPC1
NM_000271.5 missense
NM_000271.5 missense
Scores
3
15
Clinical Significance
Conservation
PhyloP100: 4.14
Genes affected
NPC1 (HGNC:7897): (NPC intracellular cholesterol transporter 1) This gene encodes a large protein that resides in the limiting membrane of endosomes and lysosomes and mediates intracellular cholesterol trafficking via binding of cholesterol to its N-terminal domain. It is predicted to have a cytoplasmic C-terminus, 13 transmembrane domains, and 3 large loops in the lumen of the endosome - the last loop being at the N-terminus. This protein transports low-density lipoproteins to late endosomal/lysosomal compartments where they are hydrolized and released as free cholesterol. Defects in this gene cause Niemann-Pick type C disease, a rare autosomal recessive neurodegenerative disorder characterized by over accumulation of cholesterol and glycosphingolipids in late endosomal/lysosomal compartments.[provided by RefSeq, Aug 2009]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -11 ACMG points.
PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000271.5
BP4
Computational evidence support a benign effect (MetaRNN=0.007890493).
BP6
Variant 18-23539384-T-C is Benign according to our data. Variant chr18-23539384-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252475.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00325 (495/152360) while in subpopulation AFR AF= 0.0113 (471/41572). AF 95% confidence interval is 0.0105. There are 4 homozygotes in gnomad4. There are 243 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 4 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.2882A>G | p.Asn961Ser | missense_variant | 19/25 | ENST00000269228.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.2882A>G | p.Asn961Ser | missense_variant | 19/25 | 1 | NM_000271.5 | P1 | |
NPC1 | ENST00000591051.1 | c.1961A>G | p.Asn654Ser | missense_variant | 12/18 | 2 | |||
NPC1 | ENST00000591075.1 | n.515A>G | non_coding_transcript_exon_variant | 1/3 | 4 |
Frequencies
GnomAD3 genomes AF: 0.00323 AC: 492AN: 152242Hom.: 4 Cov.: 33
GnomAD3 genomes
AF:
AC:
492
AN:
152242
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000848 AC: 213AN: 251206Hom.: 0 AF XY: 0.000685 AC XY: 93AN XY: 135730
GnomAD3 exomes
AF:
AC:
213
AN:
251206
Hom.:
AF XY:
AC XY:
93
AN XY:
135730
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000332 AC: 485AN: 1461402Hom.: 2 Cov.: 32 AF XY: 0.000304 AC XY: 221AN XY: 727004
GnomAD4 exome
AF:
AC:
485
AN:
1461402
Hom.:
Cov.:
32
AF XY:
AC XY:
221
AN XY:
727004
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.00325 AC: 495AN: 152360Hom.: 4 Cov.: 33 AF XY: 0.00326 AC XY: 243AN XY: 74516
GnomAD4 genome
AF:
AC:
495
AN:
152360
Hom.:
Cov.:
33
AF XY:
AC XY:
243
AN XY:
74516
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
56
ESP6500EA
AF:
AC:
0
ExAC
AF:
AC:
131
Asia WGS
AF:
AC:
3
AN:
3478
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 11, 2022 | Variant summary: NPC1 c.2882A>G (p.Asn961Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00085 in 251206 control chromosomes, predominantly at a frequency of 0.012 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in NPC1 causing Niemann-Pick Disease Type C phenotype (0.0027), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1), benign (n=1) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Oct 30, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 09, 2015 | - - |
Niemann-Pick disease, type C1 Benign:3
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 31, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Dec 28, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
MetaRNN
Benign
T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at