NM_001101648.2:c.3617T>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001101648.2(NPC1L1):​c.3617T>A​(p.Ile1206Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0117 in 1,612,224 control chromosomes in the GnomAD database, including 148 homozygotes. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0078 ( 7 hom., cov: 32)
Exomes 𝑓: 0.012 ( 141 hom. )

Consequence

NPC1L1
NM_001101648.2 missense

Scores

2
16

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: 3.96

Publications

14 publications found
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 was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0073070824).
BP6
Variant 7-44516100-A-T is Benign according to our data. Variant chr7-44516100-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 2621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NPC1L1NM_001101648.2 linkc.3617T>A p.Ile1206Asn missense_variant Exon 17 of 19 ENST00000381160.8 NP_001095118.1 Q9UHC9A0A0C4DFX6
NPC1L1NM_013389.3 linkc.3698T>A p.Ile1233Asn missense_variant Exon 18 of 20 NP_037521.2 Q9UHC9-1
NPC1L1XM_011515326.4 linkc.3422T>A p.Ile1141Asn missense_variant Exon 16 of 18 XP_011513628.1
NPC1L1XM_011515328.3 linkc.1976T>A p.Ile659Asn missense_variant Exon 14 of 16 XP_011513630.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NPC1L1ENST00000381160.8 linkc.3617T>A p.Ile1206Asn missense_variant Exon 17 of 19 1 NM_001101648.2 ENSP00000370552.3 A0A0C4DFX6
NPC1L1ENST00000289547.8 linkc.3698T>A p.Ile1233Asn missense_variant Exon 18 of 20 1 ENSP00000289547.4 Q9UHC9-1
NPC1L1ENST00000546276.5 linkc.3479T>A p.Ile1160Asn missense_variant Exon 16 of 18 1 ENSP00000438033.1 A0A0C4DGG6

Frequencies

GnomAD3 genomes
AF:
0.00777
AC:
1183
AN:
152156
Hom.:
7
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00239
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00373
Gnomad ASJ
AF:
0.00836
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00145
Gnomad FIN
AF:
0.0162
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0119
Gnomad OTH
AF:
0.00573
GnomAD2 exomes
AF:
0.00787
AC:
1946
AN:
247116
AF XY:
0.00772
show subpopulations
Gnomad AFR exome
AF:
0.00158
Gnomad AMR exome
AF:
0.00331
Gnomad ASJ exome
AF:
0.00935
Gnomad EAS exome
AF:
0.000110
Gnomad FIN exome
AF:
0.0154
Gnomad NFE exome
AF:
0.0115
Gnomad OTH exome
AF:
0.00545
GnomAD4 exome
AF:
0.0122
AC:
17758
AN:
1459950
Hom.:
141
Cov.:
33
AF XY:
0.0118
AC XY:
8547
AN XY:
726084
show subpopulations
African (AFR)
AF:
0.00191
AC:
64
AN:
33466
American (AMR)
AF:
0.00324
AC:
144
AN:
44438
Ashkenazi Jewish (ASJ)
AF:
0.0102
AC:
265
AN:
26042
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39674
South Asian (SAS)
AF:
0.00284
AC:
244
AN:
85820
European-Finnish (FIN)
AF:
0.0150
AC:
800
AN:
53284
Middle Eastern (MID)
AF:
0.000694
AC:
4
AN:
5766
European-Non Finnish (NFE)
AF:
0.0140
AC:
15512
AN:
1111136
Other (OTH)
AF:
0.0120
AC:
724
AN:
60324
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.483
Heterozygous variant carriers
0
963
1926
2888
3851
4814
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
622
1244
1866
2488
3110
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00777
AC:
1183
AN:
152274
Hom.:
7
Cov.:
32
AF XY:
0.00743
AC XY:
553
AN XY:
74452
show subpopulations
African (AFR)
AF:
0.00238
AC:
99
AN:
41554
American (AMR)
AF:
0.00373
AC:
57
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.00836
AC:
29
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5172
South Asian (SAS)
AF:
0.00145
AC:
7
AN:
4826
European-Finnish (FIN)
AF:
0.0162
AC:
172
AN:
10618
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0119
AC:
807
AN:
68024
Other (OTH)
AF:
0.00567
AC:
12
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
58
117
175
234
292
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
20
40
60
80
100
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0106
Hom.:
4
Bravo
AF:
0.00669
TwinsUK
AF:
0.0154
AC:
57
ALSPAC
AF:
0.0161
AC:
62
ESP6500AA
AF:
0.00182
AC:
8
ESP6500EA
AF:
0.0135
AC:
116
ExAC
AF:
0.00759
AC:
921
Asia WGS
AF:
0.00231
AC:
8
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Mar 29, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant 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: Frequency in ESP (all): 124/13006=0.95%; In EUR: 116/8600=1.34% -

not provided Benign:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Ezetimibe response Other:1
Feb 01, 2005
OMIM
Significance:drug response
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.39
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
20
DANN
Benign
0.97
DEOGEN2
Benign
0.21
T;T;.
Eigen
Benign
-0.23
Eigen_PC
Benign
-0.11
FATHMM_MKL
Benign
0.71
D
LIST_S2
Uncertain
0.95
D;D;D
MetaRNN
Benign
0.0073
T;T;T
MetaSVM
Benign
-0.30
T
MutationAssessor
Benign
0.74
N;.;.
PhyloP100
4.0
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-1.9
N;N;N
REVEL
Benign
0.27
Sift
Benign
0.038
D;D;D
Sift4G
Benign
0.083
T;T;T
Vest4
0.59
MVP
0.80
MPC
0.59
ClinPred
0.032
T
GERP RS
4.3
Varity_R
0.30
gMVP
0.71
Mutation Taster
=79/21
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs52815063; hg19: chr7-44555699; API