NM_001101648.2:c.3617T>A

Variant names:

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

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]

NPC1L1 links:

Genome browser will be placed here

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
NPC1L1	NM_001101648.2 link	c.3617T>A	p.Ile1206Asn	missense_variant	Exon 17 of 19	ENST00000381160.8	NP_001095118.1	Q9UHC9A0A0C4DFX6
NPC1L1	NM_013389.3 link	c.3698T>A	p.Ile1233Asn	missense_variant	Exon 18 of 20		NP_037521.2	Q9UHC9-1
NPC1L1	XM_011515326.4 link	c.3422T>A	p.Ile1141Asn	missense_variant	Exon 16 of 18		XP_011513628.1
NPC1L1	XM_011515328.3 link	c.1976T>A	p.Ile659Asn	missense_variant	Exon 14 of 16		XP_011513630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPC1L1	ENST00000381160.8 link	c.3617T>A	p.Ile1206Asn	missense_variant	Exon 17 of 19	1	NM_001101648.2	ENSP00000370552.3	A0A0C4DFX6
NPC1L1	ENST00000289547.8 link	c.3698T>A	p.Ile1233Asn	missense_variant	Exon 18 of 20	1		ENSP00000289547.4	Q9UHC9-1
NPC1L1	ENST00000546276.5 link	c.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.:

Cov.:

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.:

AF XY:

0.0118

AC XY:

8547

AN XY:

726084

show subpopulations

African (AFR)

AF:

0.00191

AC:

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:

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:

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

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

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.:

Cov.:

AF XY:

0.00743

AC XY:

553

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00238

AC:

AN:

41554

American (AMR)

AF:

0.00373

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00836

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00145

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0162

AC:

172

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0119

AC:

807

AN:

68024

Other (OTH)

AF:

0.00567

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

117

175

234

292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

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.:

Bravo

AF:

0.00669

TwinsUK

AF:

0.0154

AC:

ALSPAC

AF:

0.0161

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.0135

AC:

116

ExAC

AF:

0.00759

AC:

921

Asia WGS

AF:

0.00231

AC:

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

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.21

T;T;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.95

D;D;D

MetaRNN

Benign

0.0073

T;T;T

MetaSVM

Benign

-0.30

MutationAssessor

Benign

0.74

N;.;.

PhyloP100

4.0

PrimateAI

Benign

0.36

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

GERP RS

4.3

Varity_R

0.30

gMVP

0.71

Mutation Taster

=79/21

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over