rs10264715

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_001101648.2(NPC1L1):c.3792C>T(p.Tyr1264Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,613,972 control chromosomes in the GnomAD database, including 36,381 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.16 ( 2531 hom., cov: 32)

Exomes 𝑓: 0.21 ( 33850 hom. )

Consequence

NPC1L1
NM_001101648.2 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.25

Publications

20 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 -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 7-44515807-G-A is Benign according to our data. Variant chr7-44515807-G-A is described in ClinVar as Benign. ClinVar VariationId is 403256.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=1.25 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.226 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1L1	NM_001101648.2 link	c.3792C>T	p.Tyr1264Tyr	synonymous_variant	Exon 18 of 19	ENST00000381160.8	NP_001095118.1	Q9UHC9A0A0C4DFX6
NPC1L1	NM_013389.3 link	c.3873C>T	p.Tyr1291Tyr	synonymous_variant	Exon 19 of 20		NP_037521.2	Q9UHC9-1
NPC1L1	XM_011515326.4 link	c.3597C>T	p.Tyr1199Tyr	synonymous_variant	Exon 17 of 18		XP_011513628.1
NPC1L1	XM_011515328.3 link	c.2151C>T	p.Tyr717Tyr	synonymous_variant	Exon 15 of 16		XP_011513630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPC1L1	ENST00000381160.8 link	c.3792C>T	p.Tyr1264Tyr	synonymous_variant	Exon 18 of 19	1	NM_001101648.2	ENSP00000370552.3	A0A0C4DFX6
NPC1L1	ENST00000289547.8 link	c.3873C>T	p.Tyr1291Tyr	synonymous_variant	Exon 19 of 20	1		ENSP00000289547.4	Q9UHC9-1
NPC1L1	ENST00000546276.5 link	c.3654C>T	p.Tyr1218Tyr	synonymous_variant	Exon 17 of 18	1		ENSP00000438033.1	A0A0C4DGG6

Frequencies

GnomAD3 genomes

AF:

0.158

AC:

24021

AN:

152054

Hom.:

2532

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0516

Gnomad AMI

AF:

0.140

Gnomad AMR

AF:

0.0986

Gnomad ASJ

AF:

0.226

Gnomad EAS

AF:

0.00577

Gnomad SAS

AF:

0.109

Gnomad FIN

AF:

0.284

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.229

Gnomad OTH

AF:

0.131

GnomAD2 exomes

AF:

0.166

AC:

41709

AN:

251038

AF XY:

0.169

show subpopulations

Gnomad AFR exome

AF:

0.0462

Gnomad AMR exome

AF:

0.0771

Gnomad ASJ exome

AF:

0.217

Gnomad EAS exome

AF:

0.00234

Gnomad FIN exome

AF:

0.278

Gnomad NFE exome

AF:

0.223

Gnomad OTH exome

AF:

0.184

GnomAD4 exome

AF:

0.206

AC:

301785

AN:

1461800

Hom.:

33850

Cov.:

AF XY:

0.204

AC XY:

148396

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.0450

AC:

1506

AN:

33480

American (AMR)

AF:

0.0815

AC:

3646

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.220

AC:

5750

AN:

26134

East Asian (EAS)

AF:

0.00413

AC:

164

AN:

39700

South Asian (SAS)

AF:

0.126

AC:

10831

AN:

86254

European-Finnish (FIN)

AF:

0.275

AC:

14673

AN:

53410

Middle Eastern (MID)

AF:

0.139

AC:

802

AN:

5768

European-Non Finnish (NFE)

AF:

0.227

AC:

252771

AN:

1111940

Other (OTH)

AF:

0.193

AC:

11642

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

14303

28606

42909

57212

71515

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8464

16928

25392

33856

42320

<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:

0.158

AC:

24016

AN:

152172

Hom.:

2531

Cov.:

AF XY:

0.156

AC XY:

11606

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.0514

AC:

2137

AN:

41546

American (AMR)

AF:

0.0984

AC:

1503

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.226

AC:

785

AN:

3466

East Asian (EAS)

AF:

0.00578

AC:

AN:

5188

South Asian (SAS)

AF:

0.109

AC:

525

AN:

4826

European-Finnish (FIN)

AF:

0.284

AC:

3007

AN:

10572

Middle Eastern (MID)

AF:

0.109

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.229

AC:

15598

AN:

67980

Other (OTH)

AF:

0.128

AC:

271

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

994

1988

2983

3977

4971

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

268

536

804

1072

1340

<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:

0.184

Hom.:

5044

Bravo

AF:

0.138

Asia WGS

AF:

0.0570

AC:

197

AN:

3478

EpiCase

AF:

0.202

EpiControl

AF:

0.207

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: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 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

9.0

(source)

DANN

Benign

0.78

PhyloP100

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(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