chr7-44513605-C-T

Position:

chr7-44513605-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001101648.2(NPC1L1):c.3841G>A(p.Glu1281Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000589 in 1,613,758 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0030 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 1 hom. )

Consequence

NPC1L1
NM_001101648.2 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.0660

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0058597326).

BP6

Variant 7-44513605-C-T is Benign according to our data. Variant chr7-44513605-C-T is described in ClinVar as [Benign]. Clinvar id is 3035704.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NPC1L1	NM_001101648.2 linkuse as main transcript	c.3841G>A	p.Glu1281Lys	missense_variant	19/19	ENST00000381160.8
NPC1L1	NM_013389.3 linkuse as main transcript	c.3922G>A	p.Glu1308Lys	missense_variant	20/20
NPC1L1	XM_011515326.4 linkuse as main transcript	c.3646G>A	p.Glu1216Lys	missense_variant	18/18
NPC1L1	XM_011515328.3 linkuse as main transcript	c.2200G>A	p.Glu734Lys	missense_variant	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1L1	ENST00000381160.8 linkuse as main transcript	c.3841G>A	p.Glu1281Lys	missense_variant	19/19	1	NM_001101648.2	P1
NPC1L1	ENST00000289547.8 linkuse as main transcript	c.3922G>A	p.Glu1308Lys	missense_variant	20/20	1			Q9UHC9-1
NPC1L1	ENST00000546276.5 linkuse as main transcript	c.3703G>A	p.Glu1235Lys	missense_variant	18/18	1

Frequencies

GnomAD3 genomes

AF:

0.00300

AC:

456

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0102

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00150

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.000871

AC:

217

AN:

249164

Hom.:

AF XY:

0.000608

AC XY:

AN XY:

134872

show subpopulations

Gnomad AFR exome

AF:

0.0116

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000897

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000339

AC:

495

AN:

1461428

Hom.:

Cov.:

AF XY:

0.000263

AC XY:

191

AN XY:

727022

show subpopulations

Gnomad4 AFR exome

AF:

0.0124

Gnomad4 AMR exome

AF:

0.000783

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.000712

GnomAD4 genome

AF:

0.00299

AC:

456

AN:

152330

Hom.:

Cov.:

AF XY:

0.00306

AC XY:

228

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0102

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00425

Alfa

AF:

0.000487

Hom.:

Bravo

AF:

0.00356

ESP6500AA

AF:

0.0107

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000972

AC:

118

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

NPC1L1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.52

CADD

Benign

6.6

DANN

Benign

0.84

DEOGEN2

Benign

0.074

T;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.69

T;T;T

MetaRNN

Benign

0.0059

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.79

N;N;N

REVEL

Benign

0.052

Sift

Benign

0.80

T;T;T

Sift4G

Benign

0.23

T;T;T

Vest4

0.059

MVP

0.55

MPC

0.17

ClinPred

0.00088

GERP RS

-0.69

Varity_R

0.041

gMVP

0.43

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.

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