rs1060499885

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001101648.2(NPC1L1):​c.3086T>A​(p.Leu1029Gln) variant causes a missense change. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

NPC1L1
NM_001101648.2 missense

Scores

4
6
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.23
Variant links:
Genes affected
NPC1L1 (HGNC:7898): (NPC1 like intracellular cholesterol transporter 1) The protein encoded by this gene is a multi-pass membrane protein. It contains a conserved N-terminal Niemann-Pick C1 (NPC1) domain and a putative sterol-sensing domain (SSD) which includes a YQRL motif functioning as a plasma membrane to trans-Golgi network transport signal in other proteins. This protein takes up free cholesterol into cells through vesicular endocytosis and plays a critical role in the absorption of intestinal cholesterol. It also has the ability to transport alpha-tocopherol (vitamin E). The drug ezetimibe targets this protein and inhibits the absorption of intestinal cholesterol and alpha-tocopherol. In addition, this protein may play a critical role in regulating lipid metabolism. Polymorphic variations in this gene are associated with plasma total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels and coronary heart disease (CHD) risk. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.794

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NPC1L1NM_001101648.2 linkuse as main transcriptc.3086T>A p.Leu1029Gln missense_variant 14/19 ENST00000381160.8
NPC1L1NM_013389.3 linkuse as main transcriptc.3086T>A p.Leu1029Gln missense_variant 14/20
NPC1L1XM_011515326.4 linkuse as main transcriptc.2891T>A p.Leu964Gln missense_variant 13/18
NPC1L1XM_011515328.3 linkuse as main transcriptc.1445T>A p.Leu482Gln missense_variant 11/16

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NPC1L1ENST00000381160.8 linkuse as main transcriptc.3086T>A p.Leu1029Gln missense_variant 14/191 NM_001101648.2 P1
NPC1L1ENST00000289547.8 linkuse as main transcriptc.3086T>A p.Leu1029Gln missense_variant 14/201 Q9UHC9-1
NPC1L1ENST00000546276.5 linkuse as main transcriptc.2948T>A p.Leu983Gln missense_variant 13/181

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 29, 2016Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Not reported. No information available. Gene is associated with hyperlipidemia -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Uncertain
0.070
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.060
T;T;.
Eigen
Benign
0.15
Eigen_PC
Benign
0.18
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.89
D;D;D
M_CAP
Uncertain
0.16
D
MetaRNN
Pathogenic
0.79
D;D;D
MetaSVM
Uncertain
0.25
D
MutationAssessor
Benign
0.21
N;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Benign
0.38
T
PROVEAN
Benign
0.42
N;N;N
REVEL
Pathogenic
0.66
Sift
Benign
0.098
T;T;T
Sift4G
Uncertain
0.039
D;T;T
Polyphen
0.99
D;.;.
Vest4
0.73
MutPred
0.53
Gain of disorder (P = 0.0188);.;Gain of disorder (P = 0.0188);
MVP
0.93
MPC
0.53
ClinPred
0.83
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.22
gMVP
0.63

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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: rs1060499885; hg19: chr7-44560414; API