7-44513605-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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

Publications

6 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 -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 VariationId is 3035704.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001101648.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1L1	NM_001101648.2	MANE Select	c.3841G>A	p.Glu1281Lys	missense	Exon 19 of 19	NP_001095118.1	A0A0C4DFX6
	NPC1L1	NM_013389.3		c.3922G>A	p.Glu1308Lys	missense	Exon 20 of 20	NP_037521.2	Q9UHC9-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPC1L1	ENST00000381160.8	TSL:1 MANE Select	c.3841G>A	p.Glu1281Lys	missense	Exon 19 of 19	ENSP00000370552.3	A0A0C4DFX6
NPC1L1	ENST00000289547.8	TSL:1	c.3922G>A	p.Glu1308Lys	missense	Exon 20 of 20	ENSP00000289547.4	Q9UHC9-1
NPC1L1	ENST00000546276.5	TSL:1	c.3703G>A	p.Glu1235Lys	missense	Exon 18 of 18	ENSP00000438033.1	A0A0C4DGG6

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

GnomAD2 exomes

AF:

0.000871

AC:

217

AN:

249164

AF XY:

0.000608

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 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

African (AFR)

AF:

0.0124

AC:

414

AN:

33468

American (AMR)

AF:

0.000783

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.000185

AC:

AN:

5414

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112010

Other (OTH)

AF:

0.000712

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

130

162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.00299

AC:

456

AN:

152330

Hom.:

Cov.:

AF XY:

0.00306

AC XY:

228

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0102

AC:

423

AN:

41568

American (AMR)

AF:

0.00150

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.00425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00118

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

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

NPC1L1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.52

CADD

Benign

6.6

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.074

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0059

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-0.066

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.79

REVEL

Benign

0.052

Sift

Benign

0.80

Sift4G

Benign

0.23

Vest4

0.059

MVP

0.55

MPC

0.17

ClinPred

0.00088

GERP RS

-0.69

Varity_R

0.041

gMVP

0.43

Mutation Taster

=95/5

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over