rs120074130

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000271.5(NPC1):​c.2665G>A​(p.Val889Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Consequence

NPC1
NM_000271.5 missense

Scores

9
5
5

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.83
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a topological_domain Lumenal (size 243) in uniprot entity NPC1_HUMAN there are 84 pathogenic changes around while only 9 benign (90%) in NM_000271.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988
PP5
Variant 18-23539941-C-T is Pathogenic according to our data. Variant chr18-23539941-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2962.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NPC1NM_000271.5 linkuse as main transcriptc.2665G>A p.Val889Met missense_variant 18/25 ENST00000269228.10 NP_000262.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NPC1ENST00000269228.10 linkuse as main transcriptc.2665G>A p.Val889Met missense_variant 18/251 NM_000271.5 ENSP00000269228.4 O15118-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Niemann-Pick disease, type C1, adult form Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 01, 1999- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Pathogenic
0.52
D
BayesDel_noAF
Pathogenic
0.51
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.43
T
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D
M_CAP
Pathogenic
0.37
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.8
M
PrimateAI
Uncertain
0.66
T
PROVEAN
Benign
-1.8
N
REVEL
Pathogenic
0.81
Sift
Benign
0.21
T
Sift4G
Benign
0.16
T
Polyphen
0.99
D
Vest4
0.95
MutPred
0.94
Gain of glycosylation at P888 (P = 0.1413);
MVP
0.95
MPC
0.91
ClinPred
0.98
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.26
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs120074130; hg19: chr18-21119905; API