chr7-44515807-G-A

Position:

chr7-44515807-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_001101648.2(NPC1L1):c.3792C>T(p.Tyr1264=) 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

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 -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 id 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/exons	MANE
NPC1L1	NM_001101648.2 linkuse as main transcript	c.3792C>T	p.Tyr1264=	synonymous_variant	18/19	ENST00000381160.8
NPC1L1	NM_013389.3 linkuse as main transcript	c.3873C>T	p.Tyr1291=	synonymous_variant	19/20
NPC1L1	XM_011515326.4 linkuse as main transcript	c.3597C>T	p.Tyr1199=	synonymous_variant	17/18
NPC1L1	XM_011515328.3 linkuse as main transcript	c.2151C>T	p.Tyr717=	synonymous_variant	15/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1L1	ENST00000381160.8 linkuse as main transcript	c.3792C>T	p.Tyr1264=	synonymous_variant	18/19	1	NM_001101648.2	P1
NPC1L1	ENST00000289547.8 linkuse as main transcript	c.3873C>T	p.Tyr1291=	synonymous_variant	19/20	1			Q9UHC9-1
NPC1L1	ENST00000546276.5 linkuse as main transcript	c.3654C>T	p.Tyr1218=	synonymous_variant	17/18	1

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

GnomAD3 exomes

AF:

0.166

AC:

41709

AN:

251038

Hom.:

4542

AF XY:

0.169

AC XY:

22932

AN XY:

135690

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 SAS exome

AF:

0.120

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

Gnomad4 AFR exome

AF:

0.0450

Gnomad4 AMR exome

AF:

0.0815

Gnomad4 ASJ exome

AF:

0.220

Gnomad4 EAS exome

AF:

0.00413

Gnomad4 SAS exome

AF:

0.126

Gnomad4 FIN exome

AF:

0.275

Gnomad4 NFE exome

AF:

0.227

Gnomad4 OTH exome

AF:

0.193

GnomAD4 genome

AF:

0.158

AC:

24016

AN:

152172

Hom.:

2531

Cov.:

AF XY:

0.156

AC XY:

11606

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0514

Gnomad4 AMR

AF:

0.0984

Gnomad4 ASJ

AF:

0.226

Gnomad4 EAS

AF:

0.00578

Gnomad4 SAS

AF:

0.109

Gnomad4 FIN

AF:

0.284

Gnomad4 NFE

AF:

0.229

Gnomad4 OTH

AF:

0.128

Alfa

AF:

0.197

Hom.:

4214

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

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 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

9.0

DANN

Benign

0.78

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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