rs52815063

Positions:

chr7-44516100-A-T

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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

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 made for transcript

Verdict is Benign. Variant got -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. Variant chr7-44516100-A-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC1L1	NM_001101648.2 linkuse as main transcript	c.3617T>A	p.Ile1206Asn	missense_variant	17/19	ENST00000381160.8	NP_001095118.1	Q9UHC9A0A0C4DFX6
NPC1L1	NM_013389.3 linkuse as main transcript	c.3698T>A	p.Ile1233Asn	missense_variant	18/20		NP_037521.2	Q9UHC9-1
NPC1L1	XM_011515326.4 linkuse as main transcript	c.3422T>A	p.Ile1141Asn	missense_variant	16/18		XP_011513628.1
NPC1L1	XM_011515328.3 linkuse as main transcript	c.1976T>A	p.Ile659Asn	missense_variant	14/16		XP_011513630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NPC1L1	ENST00000381160.8 linkuse as main transcript	c.3617T>A	p.Ile1206Asn	missense_variant	17/19	1	NM_001101648.2	ENSP00000370552.3	A0A0C4DFX6
NPC1L1	ENST00000289547.8 linkuse as main transcript	c.3698T>A	p.Ile1233Asn	missense_variant	18/20	1		ENSP00000289547.4	Q9UHC9-1
NPC1L1	ENST00000546276.5 linkuse as main transcript	c.3479T>A	p.Ile1160Asn	missense_variant	16/18	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

GnomAD3 exomes

AF:

0.00787

AC:

1946

AN:

247116

Hom.:

AF XY:

0.00772

AC XY:

1031

AN XY:

133586

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 SAS exome

AF:

0.00243

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

Gnomad4 AFR exome

AF:

0.00191

Gnomad4 AMR exome

AF:

0.00324

Gnomad4 ASJ exome

AF:

0.0102

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00284

Gnomad4 FIN exome

AF:

0.0150

Gnomad4 NFE exome

AF:

0.0140

Gnomad4 OTH exome

AF:

0.0120

GnomAD4 genome

AF:

0.00777

AC:

1183

AN:

152274

Hom.:

Cov.:

AF XY:

0.00743

AC XY:

553

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00238

Gnomad4 AMR

AF:

0.00373

Gnomad4 ASJ

AF:

0.00836

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.0162

Gnomad4 NFE

AF:

0.0119

Gnomad4 OTH

AF:

0.00567

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

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

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

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Ezetimibe response

Other:1

drug response, no assertion criteria provided

literature only

OMIM

Feb 01, 2005

- -

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

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;.;.

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

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over